Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors

ABSTRACT

The present disclosure relates to certain (2S)—N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof),that inhibit dipeptidyl peptidase 1 (DPP1) activity, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), to their use in therapy, to pharmaceutical compositions containing them and to processes for preparing such compounds.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/170,641, filed Feb. 8, 2021, which is a continuation of U.S.application Ser. No. 16/855,522, filed Apr. 22, 2020, now U.S. Pat. No.11,117,874, which is a continuation of U.S. application Ser. No.16/358,091, filed Mar. 19, 2019, now U.S. Pat. No. 10,669,245, which isa continuation of U.S. application Ser. No. 15/708,634, filed Sep. 19,2017, now U.S. Pat. No. 10,287,258, which is a continuation of U.S.application Ser. No. 15/346,411, filed Nov. 8, 2016, now U.S. Pat. No.9,815,805, which is a continuation of U.S. application Ser. No.14/601,371, filed Jan. 21, 2015, now U.S. Pat. No. 9,522,894, whichclaims the benefit of priority under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 61/931,090, filed Jan. 24, 2014. Thecontents of the foregoing application are hereby incorporated byreference in their entirety.

TECHNICAL FIELD

The technical field relates to certain(2S)—N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamidecompounds (including pharmaceutically acceptable salts thereof) thatinhibit dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1) activity, to theirutility in treating and/or preventing clinical conditions includingrespiratory diseases, such as asthma and chronic obstructive pulmonarydisease (COPD), to their use in therapy, to pharmaceutical compositionscontaining them and to processes for preparing such compounds.

BACKGROUND

Dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1), also known as cathepsin C,is a lysosomal cysteine protease belonging to the papain family having amolecular weight of 200 kDa. DPP1 was first discovered by Gutman andFruton in 1948 (Biol Chem, 174, 851-858); however, the cDNA of the humanenzyme was first described in 1995 (Paris et al. 1995, FEBS Lett, 369,326-330). DPP1 is the only member of the papain family that isfunctional as a tetramer, consisting of four identical subunits. Eachsubunit is composed of an N-terminal fragment, a heavy chain and a lightchain (Dolenc et al. 1995, J Biol Chem, 270, 21626-21631).

DPP1 is constitutively expressed in many tissues with highest levels inlung, kidney, liver and spleen. DPP1 catalyses the removal of dipeptidesfrom the N-terminal end of polypeptide substrates with broadspecificity. Recent data suggest that besides being an important enzymein lysosomal protein degradation, DPP1 also functions as a key enzyme inthe activation of granule serine proteases in cytotoxic T lymphocytesand natural killer cells (granzymes A and B), mast cells (chymase andtryptase) and neutrophils (cathepsin G, neutrophil elastase andproteinase-3).

Mast cells are found in many tissues but are present in greater numbersalong the epithelial linings of the body, such as the skin, respiratorytract and gastrointestinal tract. In humans, two types of mast cellshave been identified. The T-type, which expresses only tryptase, and theMC-type, which expresses both tryptase and chymase. In humans, theT-type mast cells are located primarily in alveolar tissue andintestinal mucosa while the TC-type cells predominate in skin andconjunctiva. Tryptase and chymase appear to be important mediators ofallergic diseases, being involved in processes of inflammation,bronchoconstriction and mucus secretion.

Neutrophils play a critical role in host defence against invadingpathogens. Neutrophils are produced in the bone marrow and are fullymature when released into the circulation to take up their role as thefirst line of cellular defence. Pro-inflammatory mediators andchemotactic attractants activate neutrophils and draw them to the siteof infection, where they act to engulf bacteria by phagocytosis,assaulting them with an arsenal of anti-bacterial compounds that useboth oxidative and non-oxidative methods of attack. The powerful serineprotease, neutrophil elastase, is one of those anti-bacterial compoundsthat are clearly involved in destroying bacteria. Neutrophil elastase isreleased into the phagolysome surrounding the microorganism, which itproceeds to destroy. Neutrophil elastase is able to attack the outermembrane protein, OmpA, in gram-negative bacteria, helping to directlykill the pathogen by degrading its membrane, as well as enabling otheranti-bacterial compounds to gain access to the pathogen. In addition,neutrophil elastase may help process other anti-bacterial compounds,converting them from inactive pro-peptides into their active states,such as for cathelicidin.

Yet neutrophil elastase can also cause problems for its host. It is oneof the most destructive enzymes in the body, with the capability ofdegrading extracellular matrix proteins (including collagens,proteoglycan, fibronectin, platelet receptors, complement receptor,thrombomodulin, lung surfactant and cadherins) and key plasma proteins(including coagulation and complement factors, immunoglobulin, severalproteases and protease inhibitors). Under physiological conditions,endogenous protease inhibitors, such as al-antitrypsin, tightly regulatethe activity of neutrophil elastase. However, at inflammatory sites,neutrophil elastase is able to evade regulation, and once unregulated itcan induce the release of pro-inflammatory cytokines, such asinterleukin-6 and interleukin-8, leading to acute lung injury. It caneven impair host defence against infection by degrading phagocytesurface receptors and opsonins. Its negative role is illustrated by itsinvolvement in the tissue destruction and inflammation that characterisenumerous diseases, including hereditary emphysema, chronic obstructivepulmonary disease, cystic fibrosis, adult respiratory distress syndrome,ischemic-reperfusion injury and rheumatoid arthritis.

There is strong evidence associating tryptase and chymase with a numberof mast cell mediated allergic, immunological and inflammatory diseases.The fact that neutrophil elastase, cathepsin G and proteinase 3 alsoseem to play significant roles in these types of diseases point to DPP1being a valid therapeutic target due to its central role in activatingthese proteases (Adkison et al. 2002, J Clin Invest, 109, 363-271; Phamet al. 2004, J Immunol, 173, 7277-7281).

WO2004/110988 relate to certain nitrile derivatives and their use asDPP1 inhibitors.

WO2009/074829 relate to peptidyl nitriles and their use as DPP1inhibitors.

WO2010/128324 relate to α-amino amide nitriles and their use as DPP1inhibitors.

WO2012/119941 relate to peptidyl nitrile compounds and their use as DPP1inhibitors.

WO2013/041497 relate toN-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide andtheir use as DPP1 inhibitors.

WO2001/096285 and WO2003/048123 relate to β-amino amide nitriles thathave an inhibitory activity on cysteine proteases.

There is no disclosure of an amide nitrile compound which bears aβ-amino acid in the form of the disclosed(2S)—N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamidecompounds. We have now found that such compounds possess potent DPP1activity and/or have desirable pharmacological activity profiles (forexample a decreased risk of binding to elastin rich tissues, such as theaorta).

SUMMARY

There are provided compounds that are inhibitors of dipeptidyl peptidase1 (DPP1), their use as medicaments, pharmaceutical compositionscontaining them and synthetic routes to their production.

According to a first aspect, there is provided a compound of formula(I),

wherein

R¹ is

R² is selected from hydrogen, F, Cl, Br, OSO₂C₁₋₃alkyl or C₁₋₃alkyl;R³ is selected from hydrogen, F, Cl, Br, CN, CF₃, SO₂C₁₋₃alkyl, CONH₂ orSO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to whichthey are attached form a azetidine, pyrrolidine or piperidine ring; orR¹ is selected from

X is selected from O, S or CF₂;Y is selected from O or S;Q is selected from CH or N;R⁶ is selected from C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F and optionally by one substituent selectedfrom OH, OC₁₋₃alkyl, N(C₁₋₃alkyl)₂, cyclopropyl, or tetrapydropyran;R⁷ is selected from hydrogen, F, Cl or CH₃;or a pharmaceutically-acceptable salt thereof.The compounds disclosed are inhibitors of DPP1. Thus, the disclosedcompounds can be used as a medicament, in particular for disorders,disease or conditions responsive to inhibition of DPP1, and morespecifically respiratory diseases (such as COPD and asthma).

In another aspect, there is provided a compound of formula (I), or apharmaceutically acceptable salt of a compound of formula (I), whereinthe stereochemistry is undefined, e.g. a racemate or a mixture ofdiastereomers.

In another aspect, there is provided a pharmaceutical formulationcomprising a therapeutically effective amount of a compound of formula(I), or a pharmaceutically acceptable salt of a compound of formula (I),and a pharmaceutically acceptable diluent, excipient and/or inertcarrier.

In a further embodiment, there is provided a pharmaceutical formulationcomprising a compound of formula (I), or a pharmaceutically acceptablesalt of a compound of formula (I), for use in the treatment of acondition where inhibition of dipeptidyl peptidase 1 (DPP1) would bebeneficial.

In a further embodiment, there is provided a compound of formula (I), ora pharmaceutically acceptable salt of a compound of formula (I), for usein therapy, especially in the prevention or treatment of respiratorydisease in a mammal, particularly a human.

In a further embodiment, there is provided a compound of formula (I), ora pharmaceutically acceptable salt of a compound of formula (I), for usein therapy, especially in the prevention or treatment of asthma in amammal, particularly a human.

In a further embodiment, there is provided a compound of formula (I), ora pharmaceutically acceptable salt of a compound of formula (I), for usein therapy, especially in the prevention or treatment of COPD in amammal, particularly a human.

In a further embodiment, there is provided the use of a compound offormula (I), or a pharmaceutically acceptable salt of a compound offormula (I), for the manufacture of a medicament for the treatment andprevention of respiratory disease.

In a further embodiment, there is provided the use of a compound offormula (I), or a pharmaceutically acceptable salt of a compound offormula (I), for the manufacture of a medicament for the treatment andprevention of asthma.

In a further embodiment, there is provided the use of a compound offormula (I), or a pharmaceutically acceptable salt of a compound offormula (I), for the manufacture of a medicament for the treatment andprevention of COPD.

In still a further embodiment, administration of a compound of formula(I), or a pharmaceutically acceptable salt of a compound of formula (I)results in reduction in levels of DPP1 in a mammal, particularly ahuman.

In still a further embodiment, administration of a compound of formula(I), or a pharmaceutically acceptable salt of a compound of formula (I),results in reduction in levels of DPP1, neutrophil elastase, cathepsin Gand proteinase-3 in a mammal, particularly a human.

In still a further embodiment, administration of a compound of formula(I), or a pharmaceutically acceptable salt of a compound of formula (I),results in a reduction of DPP1 activity in a mammal, particularly ahuman.

In still a further embodiment, administration of a compound of formula(I), or a pharmaceutically acceptable salt of a compound of formula (I),results in a reduction of DPP1 activity, neutrophil elastase activity,cathepsin G activity and proteinase-3 activity in a mammal, particularlya human.

According to another aspect, there is provided a process for thepreparation of compounds of formula (I), or pharmaceutically acceptablesalts of compounds of formula (I), and the intermediates used in thepreparation thereof.

According to another aspect, there is provided a compound of formula(XXIV),

whereinR⁸ is selected from C₁₋₄ alkyl or aryl, wherein said aryl is optionallysubstituted by R¹;R⁹ and R¹⁰ taken together with the nitrogen to which they are attachedrepresent a 5- to 7-membered saturated or unsaturated ring optionallycontaining one other heteroatom which is oxygen, nitrogen or sulfur,wherein said ring is optionally fused to a (C₃-C₈)cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring;

or R⁹ and R¹⁰ taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring optionallyfused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;

or a pharmaceutically-acceptable salt thereof.

In still a further embodiment, there is provided a compound of formula(XXIV), or a pharmaceutically acceptable salt of a compound of formula(XXIV), for use in therapy, especially in the prevention or treatment ofrespiratory disease in a mammal, particularly a human.

The compounds of formula (I) herein exemplified have an IC₅₀ of lessthan 100 nmol/L for DPP1 in enzyme activity assays, for example Test A1or Test A2 described below. The compounds of formula (I) also display apromising pharmacological profiles by separating desired and undesiredeffects in vivo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction pattern for Example 2:(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,Form A.

FIG. 2 shows the X-ray powder diffraction pattern for Example 2:(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,Form B.

FIG. 3 shows the X-ray powder diffraction pattern for Example 2:(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepanecarboxamide, Form C.

FIG. 4 shows the X-ray powder diffraction pattern for Example 2:(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,xinafoate salt, Form A.

FIG. 5 shows the X-ray powder diffraction pattern for Example 2:(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,R-mandalate salt, Form A.

DETAILED DESCRIPTION

This detailed description is intended to acquaint others skilled in theart with the disclosure, its principles, and its practical applicationso that others skilled in the art may readily apply the disclosures.This description and its specific examples, while indicating embodimentsof the disclosures, are intended for purposes of illustration only.Therefore, the disclosure is not limited to the illustrative embodimentsdescribed in this specification. In addition, it is to be appreciatedthat various features of the disclosure that are, for clarity reasons,described in the context of separate embodiments, also may be combinedto form a single embodiment. Conversely, various features of thedisclosure that are, for brevity reasons, described in the context of asingle embodiment, also may be combined to form subcombinations thereof.

Listed below are definitions of various terms used in the specificationand claims to describe the present disclosure.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by “defined above” the said groupencompasses the first occurring and broadest definition as well as eachand all of the other definitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification “C₁₋₃” means a carbon group having 1, 2 or 3 carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butis not limited to, methyl, ethyl, n-propyl or i-propyl.

In this specification, unless stated otherwise, the term“pharmaceutically acceptable” is used to characterize a moiety (e.g. asalt, dosage form, or excipient) as being appropriate for use inaccordance with sound medical judgment. In general, a pharmaceuticallyacceptable moiety has one or more benefits that outweigh any deleteriouseffect that the moiety may have. Deleterious effects may include, forexample, excessive toxicity, irritation, allergic response, and otherproblems and complications.

There are disclosed compounds of formula (I) wherein R¹-R⁷, X, Y and Qare as defined in formula (I).

In one embodiment R¹ is

R² is selected from hydrogen, F, Cl, Br, OSO₂C₁₋₃alkyl, or C₁₋₃alkyl;R³ is selected from hydrogen, F, Cl, Br, CN, CF₃, SO₂C₁₋₃alkyl, CONH₂ orSO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to whichthey are attached form a azetidine, pyrrolidine or piperidine ring.

In a further embodiment R¹ is

R² is selected from hydrogen, F, Cl or C₁₋₃alkyl;R³ is selected from hydrogen, F, Cl, CN or SO₂C₁₋₃alkyl.

In still a further embodiment R¹ is

R² is selected from hydrogen, F or C₁₋₃alkyl;R³ is selected from hydrogen, F or CN.

In still a further embodiment R¹ is selected from

X is selected from O, S or CF₂;Y is selected from O or S;Q is selected from CH or N;R⁶ is selected from C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F and optionally by one substituent selectedfrom OH, OC₁₋₃alkyl, N(C₁₋₃alkyl)₂, cyclopropyl, or tetrahydropyran;R⁷ is selected from hydrogen, F, Cl or CH₃.

In still a further embodiment R¹ is selected from

X is selected from O, S or CF₂;Y is selected from O or S;R⁶ is selected from C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F and optionally by one substituent selectedfrom OH, OC₁₋₃alkyl, N(C₁₋₃alkyl)₂, cyclopropyl, or tetrahydropyran;R⁷ is selected from hydrogen, F, Cl or CH₃.

In still a further embodiment R¹ is selected from

X is selected from O, S or CF₂;R⁶ is selected from C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F;R⁷ is selected from hydrogen, F, Cl or CH₃.

In still a further embodiment R¹ is selected from

X is O;

R⁶ is selected from C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F;R⁷ is hydrogen.

In one embodiment R² is selected from hydrogen, F, Cl, Br, OSO₂C₁₋₃alkylor C₁₋₃alkyl;

In a further embodiment R² is selected from hydrogen, F, Cl orC₁₋₃alkyl.

In still a further embodiment R² is selected from hydrogen, F orC₁₋₃alkyl.

In one embodiment R³ is selected from hydrogen, F, Cl, Br, CN, CF₃,SO₂C₁₋₃alkyl, CONH₂ or SO₂NR⁴R⁵, wherein R⁴ and R⁵ together with thenitrogen atom to which they are attached form a azetidine, pyrrolidineor piperidine ring.

In a further embodiment R³ is selected from hydrogen, F, Cl, CN orSO₂C₁₋₃alkyl.

In still a further embodiment R³ is selected from hydrogen, F or CN.

In one embodiment R⁶ is selected from C₁₋₃alkyl, wherein said C₁₋₃alkylis optionally substituted by 1, 2 or 3 F and optionally by onesubstituent selected from OH, OC₁₋₃alkyl, N(C₁₋₃alkyl)₂, cyclopropyl, ortetrapydropyran.

In a further embodiment R⁶ is selected from C₁₋₃alkyl, wherein saidC₁₋₃alkyl is optionally substituted by 1, 2 or 3 F;

In still a further embodiment R⁶ is selected from methyl and ethyl.

In still a further embodiment R⁶ is methyl.

In one embodiment R⁷ is selected from hydrogen, F, Cl or CH₃.

In a further embodiment R⁷ is hydrogen.

One or more above embodiments may be combined to provide furtherspecific embodiments of the disclosure.

In one embodiment the compound of formula (I) is selected from:

-   (2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   4′-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl    methanesulfonate,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4′-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin    yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol    yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[3-(cy    clopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxy    ethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxy    ethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-2-(4′-Carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]cyanoethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-1-Cyano-2-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-2-[4′-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,-   (2S)—N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide,-   (2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,    or-   (2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,    and pharmaceutically acceptable salts thereof.

It shall be noted that any one of these specific compounds may bedisclaimed from any of the herein mentioned embodiments of thedisclosure.

Another embodiment is a product obtainable by any of the processes orexamples disclosed herein.

Pharmacological Properties

The compounds of formula (I) and their pharmaceutically acceptable saltshave activity as pharmaceuticals, in particular as inhibitors ofdipeptidyl peptidase 1 activity, and thus may be used in the treatmentof obstructive diseases of the airways including: asthma, includingbronchial, allergic, intrinsic, extrinsic, exercise-induced,drug-induced (including aspirin and NSAID-induced) and dust-inducedasthma, both intermittent and persistent and of all seventies, and othercauses of airway hyper-responsiveness; chronic obstructive pulmonarydisease (COPD); bronchitis, including infectious and eosinophilicbronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis;alpha-1 antitrypsin deficiency; farmer's lung and related diseases;hypersensitivity pneumonitis; lung fibrosis, including cryptogenicfibrosing alveolitis, idiopathic interstitial pneumonias, fibrosiscomplicating anti-neoplastic therapy and chronic infection, includingtuberculosis and aspergillosis and other fungal infections;complications of lung transplantation; vasculitic and thromboticdisorders of the lung vasculature, and pulmonary hypertension;antitussive activity including treatment of chronic cough associatedwith inflammatory and secretory conditions of the airways, andiatrogenic cough; acute and chronic rhinitis including rhinitismedicamentosa, and vasomotor rhinitis; perennial and seasonal allergicrhinitis including rhinitis nervosa (hay fever); nasal polyposis; acuteviral infection including the common cold, and infection due torespiratory syncytial virus, influenza, coronavirus (including SARS) andadenovirus, acute lung injury, acute respiratory distress syndrome(ARDS), as well as exacerbations of each of the foregoing respiratorytract disease states, in particular exacerbations of all types of asthmaor COPD.

Thus, there is provided a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as hereinbefore defined for use in therapy.

In a further aspect, there is provided the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, as hereinbeforedefined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

In particular, the compounds of the disclosure (includingpharmaceutically acceptable salts) may be used in the treatment ofasthma {such as bronchial, allergic, intrinsic, extrinsic or dustasthma, particularly chronic or inveterate asthma (for example lateasthma or airways hyper-responsiveness)}, chronic obstructive pulmonarydisease (COPD) or allergic rhinitis.

There is also provided a method of treating, or reducing the risk of, anobstructive airways disease or condition (e.g. asthma or COPD) whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as hereinbefore defined.

In a further aspect, there is provided the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, as hereinbeforedefined in the manufacture of a medicament for use in treating COPD.

In a further aspect, there is provided the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, as hereinbeforedefined in the manufacture of a medicament for use in treating asthma.

In a further aspect, there is provided the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, as hereinbeforedefined in the manufacture of a medicament for use in treating allergicrhinitis.

In a further aspect, there is provided a compound of formula (I), or apharmaceutically acceptable salt thereof as hereinbefore defined for usein treating allergic rhinitis.

In a further aspect, there is provided a compound of formula (I), or apharmaceutically acceptable salt thereof, as hereinbefore defined foruse in treating COPD.

In a further aspect, there is provided a compound of formula (I), or apharmaceutically acceptable salt thereof, as hereinbefore defined foruse in treating asthma.

Combination Therapy

The compounds of formula (I), or a pharmaceutically acceptable saltthereof, may also be administered in conjunction with other compoundsused for the treatment of the above conditions.

The disclosure further relates to a combination therapy wherein acompound of the disclosure, or a pharmaceutically acceptable saltthereof, and a second active ingredient are administered concurrently,sequentially or in admixture, for the treatment of one or more of theconditions listed above. Such a combination may be used in combinationwith one or more further active ingredients.

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a glucocorticoid receptor agonist (steroidal ornon-steroidal) such as triamcinolone, triamcinolone acetonide,prednisone, mometasone furoate, loteprednol etabonate, fluticasonepropionate, fluticasone furoate, fluocinolone acetonide, dexamethasonecipecilate, desisobutyryl ciclesonide, clobetasol propionate,ciclesonide, butixocort propionate, budesonide, beclomethasonedipropionate, alclometasone dipropionate,2,2,2-trifluoro-N-[(1S,2R)-2-[1-(4-fluorophenyl)indazol-5-yl]oxy-2-(3-methoxyphenyl)-1-methyl-ethyl]acetamide,or3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide.

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a p38 antagonist such as PH797804(3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4,N-dimethyl-benzamide),losmapimod, PF03715455(1-[5-tert-butyl-2-(3-chloro-4-hydroxy-phenyl)pyrazol-3-yl]-3-[[2-[[3-[2-(2-hydroxyethylsulfanyl)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl]phenyl]methyl]urea)orN-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-pyrazin-1-yl]benzamide.

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a phosphodiesterase (PDE) inhibitor such as amethylxanthanine including theophylline and aminophylline or a selectivePDE isoenzyme inhibitor (including a PDE4 inhibitor or an inhibitor ofthe isoform PDE4D) such as tetomilast, roflumilast, oglemilast,ibudilast, GPD-1116(3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4-one),ronomilast, NVP ABE 171(4-[8-(2,1,3-benzoxadiazol-5-yl)-1,7-naphthyridin-6-yl]benzoic acid),RPL554(2-[(2E)-9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethylurea),CHF5480([(Z)-2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)vinyl](2S)-2-(4-isobutylphenyl)propanoate),or GSK256066(6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methyl-quinoline-3-carboxamide).

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a modulator of chemokine receptor function suchas an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6,CCR7, CCR8, CCR9, CCR10 or CCR11 (for the C—C family), for example aCCR1, CCR2B or CCR5 receptor antagonist; CXCR1, CXCR2, CXCR3, CXCR4 orCXCR5 (for the C—X—C family), for example a CXCR2 or CXCR3 receptorantagonist; or CX₃CR1 for the C—X₃—C family. For example, the presentdisclosure relates to the combination of a compound of the disclosurewith PS-031291 (pyrrolidine-1,2-dicarboxylic acid2-[(4-chloro-benzyl)-methyl-amide]1-[(4-trifluoromethyl-phenyl)-amide]), CCX-354(1-[4-(4-chloro-3-methoxy-phenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone),vicriviroc, maraviroc, cenicriviroc, navarixin(2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5-methyl-2-furyl)propyl]amino]-3,4-dioxo-cyclobuten-1-yl]amino]benzamide),SB656933(1-(2-chloro-3-fluoro-phenyl)-3-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonyl-phenyl)urea),N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(1R,2S)-2,3-dihydroxy-1-methyl-propoxy]pyrimidin-4-yl]azetidine-1-sulfonamide,N-[6-[(1R,2S)-2,3-dihydroxy-1-methyl-propoxy]-2-[(4-fluorophenyl)methylsulfanyl]pyrimidin-4-yl]-3-methyl-azetidine-1-sulfonamideorN-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(1R,2R)-2,3-dihydroxy-1-methyl-propyl]amino]pyrimidin-4-yl]azetidine-1-sulfonamide.

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a leukotriene biosynthesis inhibitor,5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein(FLAP) antagonist such as TA270(4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone),PF-4191834 (2H-pyran-4-carboxamide,tetrahydro-4-[3-[[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl]-),setileuton, CMI977(1-[4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydrofuran-2-yl]but-3-ynyl]-1-hydroxy-urea),fiboflapon(3-[3-tert-butylsulfanyl-1-[[4-(6-ethoxy-3-pyridyl)phenyl]methyl]-5-[(5-methyl-2-pyridyl)methoxy]indol-2-yl]-2,2-dimethyl-propanoicacid), GSK2190915 (1H-indole-2-propanoic acid,3-[(1,1-dimethylethyl)thio]-1-[[4-(6-methoxy-3-pyridinyl)phenyl]methyl]-α,α-dimethyl-5-[(2-pyridinyl)methoxy]-),licofelone, quiflapon(3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-(2-quinolylmethoxy)indol-2-yl]-2,2-dimethyl-propanoicacid), veliflapon((2R)-2-cyclopentyl-2-[4-(2-quinolylmethoxy)phenyl]acetic acid), ABT080(4,4-bis[4-(2-quinolylmethoxy)phenyl]pentanoic acid), zileuton,zafirlukast, or montelukast.

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a CRTh2 antagonist or a DP2 antagonist such asACT129968(2-[2-[(5-acetyl-2-methoxy-phenyl)methylsulfanyl]fluoro-benzimidazol-1-yl]aceticacid), AMG853(2-[4-[4-(tert-butylcarbamoyl)-2-[(2-chloro-4-cyclopropyl-phenyl)sulfonylamino]phenoxy]-5-chloro-2-fluoro-phenyl]aceticacid), AM211(2-[3-[2-[[benzylcarbamoyl(ethyl)amino]methyl]-4-(trifluoromethyl)phenyl]-4-methoxy-phenyl]aceticacid),2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methyl-indol-1-yl]aceticacid,(2S)-2-[4-chloro-2-(2-chloro-4-ethylsulfonyl-phenoxy)phenoxy]propanoicacid,2-[4-chloro-2-[2-fluoro-4-(4-fluorophenyl)sulfonyl-phenyl]phenoxy]aceticacid, or(2S)-2-[2-[3-chloro-4-(2,2-dimethylpyrrolidine-1-carbonyl)phenyl]-4-fluoro-phenoxy]propanoicacid.

The present disclosure still further relates to the combination of acompound of the disclosure, or a pharmaceutically acceptable saltthereof, together with a myeloperoxidase antagonist such as resveratrol,piceatannol, or1-(2-isopropoxyethyl)-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one.

In a further aspect of the present disclosure, there is provided apharmaceutical composition (for example, for use as a medicament for thetreatment of one of the diseases or conditions listed herein, such asCOPD, asthma or allergic rhinitis) comprising a compound of thedisclosure, or a pharmaceutically acceptable salt thereof, and at leastone active ingredient selected from:

-   -   a) a toll-like receptor agonist (such as a TLR7 or TLR9 agonist)    -   b) an adenosine antagonist;    -   c) a glucocorticoid receptor agonist (steroidal or        non-steroidal);    -   d) a p38 antagonist;    -   e) a PDE4 antagonist;    -   f) a modulator of chemokine receptor function (such as a CCR1,        CCR2B, CCR5, CXCR2 or CXCR3 receptor antagonist); or    -   g) a CRTh2 antagonist;    -   as defined above.

In one embodiment the compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, is administered concurrently or sequentiallywith one or more further active ingredients selected from those definedabove. For example, the compound of the disclosure, or apharmaceutically acceptable salt thereof, may be administeredconcurrently or sequentially with a further pharmaceutical compositionfor use as a medicament for the treatment of one of the diseases orconditions listed herein, such as a respiratory tract condition (e.g.COPD, asthma or allergic rhinitis). Said further pharmaceuticalcomposition may be a medicament which the patient may already beprescribed (e.g. an existing standard or care medication), and mayitself be a composition comprising one or more active ingredientsselected from those defined above.

Pharmaceutical Compositions

For the above-mentioned therapeutic uses the dosage administered willvary with the compound employed, the mode of administration, thetreatment desired and the disorder indicated. For example, the dailydosage of the compound of the disclosure, if inhaled, may be in therange from 0.05 micrograms per kilogram body weight (μg/kg) to 100micrograms per kilogram body weight (μg/kg). Alternatively, if thecompound is administered orally, then the daily dosage of the compoundof the disclosure may be in the range from 0.01 micrograms per kilogrambody weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I), or pharmaceutically acceptable saltsthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).Conventional procedures for the selection and preparation of suitablepharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 2^(nd) Ed. 2002.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present disclosure also provides pharmaceutical composition(s)comprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as hereinbefore defined in association withpharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s).

The disclosure further provides a process for the preparation of apharmaceutical composition of the disclosure which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,as hereinbefore defined with a pharmaceutically acceptable adjuvant(s),diluents(s) or carrier(s).

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powderformulations, for example, formulations in the inhaler device known asthe Turbuhaler®; or systemically, e.g. by oral administration in theform of tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); or by rectal administration in the form ofsuppositories.

For oral administration the compound of the disclosure may be admixedwith adjuvant(s), diluent(s) or carrier(s), for example, lactose,saccharose, sorbitol, mannitol; starch, for example, potato starch, cornstarch or amylopectin; cellulose derivative; binder, for example,gelatine or polyvinylpyrrolidone; disintegrant, for example cellulosederivative, and/or lubricant, for example, magnesium stearate, calciumstearate, polyethylene glycol, wax, paraffin, and the like, and thencompressed into tablets. If coated tablets are required, the cores,prepared as described above, may be coated with a suitable polymerdissolved or dispersed in water or readily volatile organic solvent(s).Alternatively, the tablet may be coated with a concentrated sugarsolution which may contain, for example, gum arabic, gelatine, talcumand titanium dioxide.

For the preparation of soft gelatine capsules, the compound of thedisclosure may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using pharmaceutical excipients like the above-mentionedexcipients for tablets. Also liquid or semisolid formulations of thecompound of the disclosure may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups,solutions or suspensions. Solutions, for example may contain thecompound of the disclosure, the balance being sugar and a mixture ofethanol, water, glycerol and propylene glycol. Optionally such liquidpreparations may contain coloring agents, flavoring agents, saccharineand/or carboxymethylcellulose as a thickening agent. Furthermore, otherexcipients known to those skilled in art may be used when makingformulations for oral use.

Preparation of Compounds

The present disclosure further provides a process for the preparation ofa compound of formula (I) as defined above.

General Preparation

The skilled person will recognise that the compounds of the disclosuremay be prepared, in known manner, in a variety of ways. The routes beloware merely illustrative of some of the methods that can be employed forthe synthesis of compounds of formula (I).

The present disclosure further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt thereofas defined above which comprises reacting a compound of formula (II),

wherein R¹ is as defined in formula (I), with a compound of formula(III),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl), andoptionally thereafter carrying out one or more of the followingprocedures:

-   -   converting a compound of formula (I) into another compound of        formula (I)    -   removing any protecting groups    -   forming a pharmaceutically acceptable salt.

The process is conveniently carried out in the presence of a base suchas DiPEA or TEA and one or more activating agents such as EDCI,2-pyridinol-1-oxide, or T3P. The reaction is conveniently carried out inan organic solvent such as DMF or DCM at a temperature, for example, inthe range from 20° C. to 100° C., in particular at ambient temperature(25° C.).

Compounds of formula (II) may be prepared by reaction of a compound offormula (IV),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl),with a suitable reagent to remove the protecting group PG. An example ofa suitable reagent is formic acid.

Compounds of formula (IV) may be prepared by reacting a compound offormula (V),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl) andHal represents a halogen (e.g. I or Br), with a compound of formula (VI)or an ester thereof,

wherein R¹ is as defined in formula (I), in the presence of a catalystsuch as Pd(dppf)Cl₂.DCM or 1,1 bis(di-tert-butylphosphino)ferrocenepalladium dichloride and a base such as potassium carbonate or sodiumcarbonate. The reaction is conveniently carried out in a solvent such asdioxane/water mixture or ACN/water mixture at a temperature, forexample, in the range from 20° C. to 100° C., particularly at 75° C.

Compounds of formula (V) may be prepared from a compound of formula(VII),

in which PG represents a protecting group (e.g. tert-butoxycarbonyl) andHal represents a halogen (e.g. I or Br), using standard literatureprocedures for the dehydration of an amide, for example with Burgessreagent, or with a reagent such as T3P with or without a base such asDiPEA, in a solvent such as DCM or DMF at a temperature in the rangefrom −20° C. to 100° C., for example at 0° C.

Compounds of formula (VII) may be prepared by reacting a compound offormula (VIII),

in which PG represents a protecting group (e.g. tert-butoxycarbonyl) andHal represents a halogen (e.g. I or Br), with an aqueous ammoniasolution, using standard literature procedures for the formation of anamide, for example, in the presence of a base such as N-ethyl-morpholineor DiPEA and an activating agent such as TBTU or T3P. The reaction isconveniently carried out in an organic solvent such as DMF, at atemperature in the range from −20° C. to 100° C., for example at 0° C.

Compounds of formula (VIII) are either commercially available, are knownin the literature (e.g. from Tetrahedron: Asymmetry, 1998, 9, 503) ormay be prepared using known techniques.

There is further provided a process for the preparation of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as definedabove which comprises reacting a compound of formula (IX),

wherein R¹ is as defined above and PG represents a protecting group(e.g. tert-butoxycarbonyl), using standard literature procedures for thedehydration of an amide, for example with Burgess reagent or with areagent such as T3P with or without a base such as DiPEA, in a solventsuch as DCM or DMF at a temperature in the range from −20° C. to 100°C., for example at 25° C., and thereafter reacting with a suitablereagent to remove the protecting group PG. An example of a suitablereagent is formic acid.

A compound of formula (IX) may be prepared by reacting a compound offormula (X), wherein PG represents a protecting group (e.g.tert-butoxycarbonyl),

with a halide of formula (XI), wherein R¹ is defined as in formula (I),

R¹—Br/I  (XI),

in the presence of a catalyst such asbis[bis(1,2-diphenylphosphino)ethane]palladium(0), or Pd(dppf)Cl₂.DCM,and a base such as potassium carbonate or sodium carbonate. The reactionis conveniently carried out in a solvent such as dioxane/water mixtureor ACN/water mixture at a temperature, for example, in the range from20° C. to 100° C., particularly at 80° C.

A compound of formula (X) may be prepared by reacting a compound offormula (XII), wherein PG represents a protecting group (e.g.tert-butoxycarbonyl),

with B₂Pin₂ in the presence of a suitable catalyst such asPd(dppf)Cl₂.DCM and with or without 1,1′-bis(diphenylphosphino)ferroceneor 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride, with asuitable salt such as potassium acetate, in a solvent such as DMSO at atemperature in the range 60° C. to 100° C., for example at 85° C.

A compound of formula (XII) may be prepared by reacting a compound offormula (XIII),

with a compound of formula (III),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl) inthe presence of a base such as DiPEA or TEA and an activating agent suchas EDCI, 2-pyridinol-1-oxide, or T3P. The reaction is convenientlycarried out in an organic solvent such as DMF or DCM at a temperature,for example, in the range from 20° C. to 100° C., in particular atambient temperature (25° C.).

Compounds of formula (XIII) may be prepared by reacting a compound offormula (XIV),

in which PG is as defined in formula (VII), with an aqueous ammoniasolution, using standard literature procedures for the formation of anamide, for example, in the presence of a base such as N-ethyl-morpholineor DiPEA and an activating agent such as a “uronium” reagent (forexample TBTU), or T3P. The reaction is conveniently carried out in anorganic solvent such as DMF, at a temperature in the range from −20° C.to 100° C., for example at 0° C.

A compound of formula (IX) may be prepared by reacting a compound offormula (XII) wherein PG represents a protecting group (e.g.tert-butoxycarbonyl), with a compound of formula (VI) or a boronateester thereof, in the presence of a catalyst such asbis[bis(1,2-diphenylphosphino)ethane]palladium(0) or Pd(dppf)Cl₂.DCM anda base such as potassium carbonate or sodium carbonate. The reaction isconveniently carried out in a solvent such as dioxane/water or ACN/watermixture at a temperature, for example, in the range from 20° C. to 100°C., particularly at 80° C.

There is further provided a process for the preparation of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as definedabove which comprises reacting a compound of formula (XV),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl),with a compound of formula (VI) or an ester thereof, wherein R¹ is asdefined in formula (I), in the presence of a catalyst such asPd(dppf)Cl₂.DCM or 1,1 bis(di-tert-butylphosphino)ferrocene palladiumdichloride and a base such as potassium carbonate or sodium carbonate.The reaction is conveniently carried out in a solvent such asdioxane/water mixture or ACN/water mixture at a temperature, forexample, in the range from 20° C. to 100° C., particularly at 75° C.,and thereafter reacting with a suitable reagent to remove the protectinggroup PG. An example of a suitable reagent is formic acid.

Compounds of formula (XV) may be prepared from compounds of formula(XII) using standard literature procedures for the dehydration of anamide, for example with Burgess reagent or a reagent such as TBTU or T3Pwith or without a base such as DiPEA, in a solvent such as DCM or DMF ata temperature in the range from −20° C. to 100° C., for example at 25°C.

There is further provided a process for the preparation of a compound offormula (I) or a pharmaceutically acceptable salt thereof as definedabove which comprises reacting a compound of formula (XVI),

wherein R¹ is as defined in formula (I), with a compound of formula(III), conveniently carried out in the presence of a base such as DiPEAor TEA and one or more activating agents such as EDCI,2-pyridinol-1-oxide, or T3P, followed by a dehydrating reagent such asT3P. The reaction is conveniently carried out in an organic solvent suchas DMF or DCM at a temperature, for example, in the range from 20° C. to100° C., in particular at ambient temperature (25° C.).

Compounds of formula (XVI) can be prepared from reacting compounds offormula (VII) with compounds of formula (VI) or an ester thereof,wherein R¹ is as defined in formula (I), in the presence of a catalystsuch as Pd(dppf)Cl₂.DCM or 1,1 bis(di-tert-butylphosphino)ferrocenepalladium dichloride and a base such as potassium carbonate or sodiumcarbonate. The reaction is conveniently carried out in a solvent such asdioxane/water mixture or ACN/water mixture at a temperature, forexample, in the range from 20° C. to 100° C., particularly at 75° C.,followed by deprotection of PG.

A compound of formula (III),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl) iseither commercially available, or may be prepared from a compound offormula (XVII),

using literature procedures for mild ester hydrolysis (e.g. from Tetr.Lett., 2007, 48, 2497), for example with LiBr and a base such as TEA, ina solvent such as ACN/water mixture, for example at 25° C.

A compound of formula (XVII), wherein PG represents a protecting group(e.g. tert-butoxycarbonyl), may be prepared from a compound of formula(XVIII),

using a reducing agent, for example BH₃-DMS, in a solvent such as THF,at a temperature in the range from 0 to 40° C., for example at 25° C.

A compound of formula (XVIII), wherein PG represents a protecting group(e.g. tert-butoxycarbonyl), may be prepared from a compound of formula(XIX), using a biocatalytic transformation for chemoselective lactamformation, for example using a lipase such as Novozym 435, in a solventsuch as an ether, e.g. dioxane, at a temperature in the range from 0 to80° C., for example at 55° C., followed by conditions for introductionof the protecting group PG.

A compound of formula (XIX) may be prepared from a compound of formula(XX),

wherein PG¹ and PG² represent protecting groups (e.g. bensyl), usingconditions for hydrogenation, for example using H₂ (g), and a reagentsuch as palladium dihydroxide on carbon, in a solvent such as methanolor dioxane, under a pressure of for example 10 bar, at a temperature inthe range from 25 to 80° C., for example at 40° C.

A compound of formula (XX), wherein PG¹ and PG² represent protectinggroups (e.g. bensyl), may be prepared from a compound of formula (XXI),

wherein PG¹ and PG² represent protecting groups (e.g. bensyl), usingconditions for Oxa-Michael reaction, reacting with methyl propynoate, inpresence of a base such as 4-methylmorpholine, in a solvent such astoluene, at a temperature in the range from 0 to 100° C., for example at25° C.

A compound of formula (XXI), wherein PG¹ and PG² represent protectinggroups (e.g. bensyl), may be prepared from reacting a diprotected bensylamine (e.g. dibenzylamine) with (S)-methyl oxirane-2-carboxylate, in asolvent such as ethanol, at a temperature in the range from 0 to 78° C.,for example at 70° C.

Alternatively, a compound of formula (III),

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl) maybe prepared from oxidation of a compound of formula (XXII),

for example using reagents such as TEMPO, and sodium hypochlorite,optionally in presence of a salt such as sodium bromide, in a solventsuch as DCM/water, and in presence of a buffer such as NaHCO₃, and aphase transfer catalyst such as tetrabutylammonium bisulphate, at atemperature in the range from 0 to 100° C., for example at 25° C.

A compound of formula (XXII), wherein PG represents a protecting group(e.g. tert-butoxycarbonyl) may be prepared from a compound of formula(XXIII),

wherein PG¹ and PG² represent protecting groups (e.g. bensyl), reactingwith a base such as sodium hydride, in a solvent such as THF, at atemperature in the range from 0 to 60° C., for example at 25° C.,followed by interconversion of protecting groups PG, PG¹ and PG², asdefined in formula (XXII) and (XXIII).

A compound of formula (XXIII), wherein PG¹ and PG² represent protectinggroups (e.g. bensyl), may be prepared from reacting protected3-aminopropanol (e.g. N-bensyl-3-aminopropanol) with(S)-2-((benzyloxy)methyl)oxirane, in a solvent such as ethanol orpropanol, at a temperature in the range from 0 to 70° C., for example at40° C., followed by reacting the crude product with methanesulfonylchloride, in presence of a base such as DiPEA, in a solvent such as DCM,at a temperature in the range from −10 to 25° C., for example at −5° C.

Compounds of formula (VI) or an ester thereof, (VIII), (XI) and (XIV)are either commercially available, are known in the literature or may beprepared using known techniques.It will be appreciated by those skilled in the art that in the processesof the present disclosure certain functional groups such as hydroxyl oramino groups in the reagents may need to be protected by protectinggroups. Thus, the preparation of the compounds of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups.

The skilled person will recognise that at any stage of the preparationof the compounds of formula (I), mixtures of isomers (e.g. racemates) ofcompounds corresponding to any of formulae (II)-(V), (VII)-(X) and(XXII)-(XVI) may be utilized. At any stage of the preparation, a singlestereoisomer may be obtained by isolating it from a mixture of isomers(e.g., a racemate) using, for example, chiral chromatographicseparation.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, 4^(th) Ed, T. W. Greene and P.G. M. Wuts, Wiley (2006) and ‘Protecting Groups’, 3^(rd) Ed P. J.Kocienski, Georg Thieme Verlag (2005).

A further embodiment encompasses pharmaceutically acceptable salts ofthe compounds of formula (I).

A salt of a compound of formula (I) may be advantageous due to one ormore of its chemical or physical properties, such as stability indiffering temperatures and humidities, or a desirable solubility in H₂O,oil, or other solvent. In some instances, a salt may be used to aid inthe isolation or purification of the compound. In some embodiments(particularly where the salt is intended for administration to ananimal, e.g. a human, or is a reagent for use in making a compound orsalt intended for administration to an animal), the salt ispharmaceutically acceptable.

Where the compound of formula (I) is sufficiently acidic,pharmaceutically acceptable salts include, but are not limited to, analkali metal salt, e.g. Na or K, an alkali earth metal salt, e.g. Ca orMg, or an organic amine salt. Where the compound of formula (I) issufficiently basic, pharmaceutically acceptable salts include, but arenot limited to, inorganic or organic acid addition salts.

There may be more than one cation or anion depending on the number ofcharged functions and the valency of the cations or anions.

For reviews on suitable salts, see Berge et al., J. Pharm. Sci., 1977,66, 1-19 or “Handbook of Pharmaceutical Salts: Properties, selection anduse”, P. H. Stahl, P. G. Vermuth, IUPAC, Wiley-VCH, 2002.

In a salt proton transfer occurs between the compound of formula (I) andthe counter ion of the salt. However, in some cases proton transfer maynot be complete and the solid is not therefore a true salt. In suchcases the compound of formula (I) and the “co-former” molecules in thesolid primarily interact through non-ionic forces such as hydrogenbonding. It is accepted that the proton transfer is in fact a continuum,and can change with temperature, and therefore the point at which a saltis better described as a co-crystal can be somewhat subjective.

Where an acid or base co-former is a solid at rt and there is no or onlypartial proton transfer between the compound of formula (I) and such anacid or base co-former, a co-crystal of the co-former and compound offormula (I) may result rather than a salt. All such co-crystal forms ofthe compound of formula (I) are encompassed by the present disclosure.

The compounds of formula (I) may form mixtures of its salt andco-crystal forms. It is also to be understood that the presentdisclosure encompasses salt/co-crystal mixtures of the compound offormula (I).

Salts and co-crystals may be characterized using well known techniques,for example X-ray powder diffraction, single crystal X-ray diffraction(for example to evaluate proton position, bond lengths or bond angles),solid state NMR, (to evaluate for example, C, N or P chemical shifts) orspectroscopic techniques (to measure for example, O—H, N—H or COOHsignals and IR peak shifts resulting from hydrogen bonding).

It is also to be understood that certain compounds of formula (I) mayexist in solvated form, e.g. hydrates, including solvates of apharmaceutically acceptable salt of a compound of formula (I).

In a further embodiment, certain compounds of formula (I) may exist asracemates and racemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. It is to be understood thatthe present disclosure encompasses all such isomeric forms. Certaincompounds of formula (I) may also contain linkages (e.g. carbon-carbonbonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotationis restricted about that particular linkage, e.g. restriction resultingfrom the presence of a ring bond or double bond. Accordingly, it is tobe understood that the present disclosure encompasses all such isomers.Certain compound of formula (I) may also contain multiple tautomericforms. It is to be understood that the present disclosure encompassesall such tautomeric forms. Stereoisomers may be separated usingconventional techniques, e.g. chromatography or fractionalcrystallization, or the stereoisomers may be made by stereoselectivesynthesis.

In a further embodiment, the compounds of formula (I) encompass anyisotopically-labeled (or “radio-labelled”) derivatives of a compound offormula (I). Such a derivative is a derivative of a compound of formula(I) wherein one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numbertypically found in nature. Examples of radionuclides that may beincorporated include ²H (also written as “D” for deuterium).

In a further embodiment, the compounds of formula (I) may beadministered in the form of a prodrug which is broken down in the humanor animal body to give a compound of the formula (I). Examples ofprodrugs include in vivo hydrolysable esters of a compound of theformula (I).

An in vivo hydrolysable (or cleavable) ester of a compound of theformula (I) that contains a carboxy or a hydroxy group is, for example,a pharmaceutically acceptable ester which is hydrolyzed in the human oranimal body to produce the parent acid or alcohol. For examples of esterprodrugs derivatives, see: Curr. Drug. Metab. 2003, 4, 461.Various other forms of prodrugs are known in the art. For examples ofprodrug derivatives, see: Nature Reviews Drug Discovery 2008, 7, 255 andreferences cited therein.

EXAMPLES

The disclosure will now be further explained by reference to thefollowing non limiting examples.

(i) Unless stated otherwise, ¹H NMR spectra were recorded on BrukerAvance III spectrometers operating at a field strength of 400, 500 or600 MHz. Either the central peaks of chloroform-d (CDCl₃; δ_(H) 7.27ppm), dimethylsulfoxide-d₆ (d₆-DMSO; δ_(H) 2.50 ppm) or methanol-d₄(CD₃OD; δ_(H) 3.31 ppm) were used as references.(ii) MS spectra were either recorded on a Micromass ZQ single quadrapoleLC-MS or Quattro Micro LC-MS-MS, following analytical HPLC, using aPhenomenex Luna 5μ C18 (2), 100×4.6 mm. (plus guard cartridge) column,and a gradient of ACN containing 0.1% formic acid in 0.1% aq formicacid, or a Waters Xterra MS 5μ C18, 100×4.6 mm. (plus guard cartridge)column, and a gradient of ACN in 10 mM aq ammonium hydrogen carbonate.Ionisation was routinely ESCI an option which gives both ESI and APCIdata from a single run. Alternatively, LC-MS experiments were performedusing a Waters Acquity UPLC system combined with a Waters Xevo Q-ToFMass Spectrometer in ESI mode. The UPLC system was equipped with both aBEH C18 column (1.7 μm, 2.1×50 mm) in combination with a 46 mM ammoniumcarbonate/NH₃ buffer at pH 10, and an HSS C18 column (1.8 μm, 2.1×50 mm)in combination with 10 mM formic acid, 1 mM ammonium formate buffer atpH 3. Where values for m/z are given, generally only ions which indicatethe parent mass are reported, and the mass ions quoted are the positiveor negative mass ions: [M]⁺, [M+H]⁺, [M−H]⁻ or [M+2H-BOC]⁺.(iii) The title and sub-title compounds of the examples and preparationswere named using the IUPAC name program ACD/Name 2012 from Acdlabs.(iv) Unless stated otherwise, starting materials were commerciallyavailable, and all solvents and commercial reagents were of laboratorygrade and used as received. Unless stated otherwise, operations werecarried out at ambient temperature, i.e. in the range between 17-28° C.and, where appropriate, under an atmosphere of an inert gas such asnitrogen.(iv) The X-ray diffraction analysis was performed according to standardmethods, which can be found in e.g. Kitaigorodsky, A. I. (1973),Molecular Crystals and Molecules, Academic Press, New York; Bunn, C. W.(1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley &Sons, New York.Samples were mounted on single silicon crystal (SSC) wafer mounts andpowder X-ray diffraction was recorded with a PANalytical X'Pert PRO(reflection geometry, wavelength of X-rays 1.5418 Å nickel-filtered Curadiation, Voltage 45 kV, filament emission 40 mA). Automatic variabledivergence and anti scatter slits were used and the samples were rotatedduring measurement. Samples were scanned from 2-50° 2Theta using a0.013° step width and 116 or 233 seconds count time using a PIXCELdetector (active length 3.35° 2Theta). It is known in the art that anX-ray powder diffraction pattern may be obtained which has one or moremeasurement errors depending on measurement conditions (such asequipment, sample preparation or machine used). In particular, it isgenerally known that intensities in an X-ray powder diffraction patternmay fluctuate depending on measurement conditions and samplepreparation. For example, persons skilled in the art of X-ray powderdiffraction will realise that the relative intensities of peaks may varyaccording to the orientation of the sample under test and on the typeand setting of the instrument used. The skilled person will also realisethat the position of reflections can be affected by the precise heightat which the sample sits in the diffractometer and the zero calibrationof the diffractometer. The surface planarity of the sample may also havea small effect. Hence a person skilled in the art will appreciate thatthe diffraction pattern data presented herein is not to be construed asabsolute and any crystalline form that provides a power diffractionpattern substantially identical to those disclosed herein fall withinthe scope of the present disclosure (for further information seeJenkins, R & Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’John Wiley & Sons, 1996).Generally, a measurement error of a diffraction angle in an X-ray powderdiffractogram may be approximately plus or minus 0.1° 2-theta, and sucha degree of a measurement error should be taken into account whenconsidering the X-ray powder diffraction data. Furthermore, it should beunderstood that intensities might fluctuate depending on experimentalconditions and sample preparation (e.g. preferred orientation). Thefollowing definitions have been used for the relative intensity (%):81-100%, vs (very strong); 41-80%, str (strong); 21-40%, med (medium);10-20%, w (weak); 1-9%, vw (very weak).The following abbreviations are used:

ACN Acetonitrile Burgess reagent MethylN-(triethylammoniumsulfonyl)carbamate BH₃-DMS Borane dimethyl sulfidecomplex CDI 1,1′-Carbonyldiimidazole DCM Dichloromethane DMFN,N-Dimethylformamide DMSO Dimethyl sulfoxide DiPEADiisopropylethylamine (Hunig's base) EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc Ethylacetate g Gram(s) h Hour(s) HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate) HPLC High performance liquid chromatographyL Litre(s) LC Liquid chromatography LCMS Liquid chromatography-massspectroscopy min Minute(s) mL Milliliter(s) MTBE Methyl tert-butyl etherPd(dppf)Cl₂•DCM[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane Pin₂B₂ Bis (pinacolato) diboron rt Room temperatureT3P Propylphosphonic anhydride TBTUO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateTCNB 1,2,4,5-Tetrachloro-3-nitrobenzene TEA Triethylamine TEMPO2,2,6,6-Tetramethylpiperidine 1-oxyl THF Tetrahydrofuran XPhos2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Preparation of Boronate Ester Intermediates Boronate Ester 15-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3,7-dimethyl-1,3-benzoxazol-2(3H)-onei) 5-Chloro-7-methyl-1,3-benzoxazol-2(3H)-one

CDI (3.09 g, 19.0 mmol) was added to a solution of2-amino-4-chloro-6-methylphenol (2.5 g, 15.9 mmol) in THF (65 mL). Thereaction was heated at reflux for 2.5 h before cooling to rt. Thereaction mixture was transferred to a separating funnel and diluted withEtOAc (100 mL). The mixture was washed sequentially with 2 Mhydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution. The organic extractwas dried (sodium sulfate), filtered and concentrated under reducedpressure to afford the subtitled compound as a light brown solid (2.89g, 98%). ¹H NMR (400 MHz, DMSO-d₆): 11.84 (s, 1H), 7.10 (d, 1H), 7.06(d, 1H), 2.37 (s, 3H).

ii) 5-Chloro-3,7-dimethyl-1,3-benzoxazol-2(3H)-one

Cesium carbonate (2.65 g, 8.12 mmol) was added to a solution of5-chloro-7-methyl-1,3-benzoxazol-2(3H)-one (1.50 g, 8.12 mmol) in DMF(100 mL). After 20 min methyl iodide (0.61 mL, 9.84 mmol) was addeddropwise and stirred at rt for 2 h before pouring onto ice-water (100mL). The resultant brown precipitate was collected by filtration anddried in a vacuum oven to afford the subtitled compound as a brown solid(1.6 g, 100%).

¹H NMR (400 MHz, DMSO-d₆): 7.27 (s, 1H), 7.07 (s, 1H), 2.31 (s, 3H) (oneCH₃ under water peak)

iii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3,7-dimethyl-1,3-benzoxazol-2(3H)-one

Bis(neopentyl glycolato)diboron (342 mg, 1.52 mmol) and potassiumacetate (198 mg, 2.02 mmol) were added to a solution of5-chloro-3,7-dimethyl-1,3-benzoxazol-2(3H)-one (200 mg, 1.01 mmol) in1,4-dioxane (5 mL). The reaction mixture was degassed under nitrogen for15 min before XPhos (19 mg, 0.040 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos-Pd-G2, 16 mg, 0.020 mmol) were added. The reaction mixture washeated at 80° C. for 3 h. After this time the reaction mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography eluting with 0-20% EtOAc in iso-hexane to afford thetitle compound as a light brown oil (184 mg, 66%). ¹H NMR (400 MHz,CDCl₃): δ 7.44 (s, 1H), 7.23 (s, 1H), 3.80 (s, 4H), 3.40 (s, 3H), 2.39(s, 3H), 1.04 (s, 6H).

Boronate Ester 27-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinoxalin-2(1H)-one

Bis(neopentyl glycolato)diboron (1.42 mg, 6.30 mmol) and potassiumacetate (823 mg, 8.40 mmol) were added to a solution of7-bromo-1-methylquinoxalin-2(1H)-one (1.0 g, 4.2 mmol) in 1,4-dioxane(15 mL). The reaction mixture was degassed under nitrogen for 30 minbefore Pd(dppf)Cl₂.DCM (171 mg, 0.21 mmol) was added. The reactionmixture was heated at 80° C. for 3 h. After this time the reactionmixture was concentrated under reduced pressure and purified by silicagel column chromatography eluting with 30% EtOAc in iso-hexane to affordan orange solid. Trituration with diethyl ether afforded the titlecompound as an off-white solid (340 mg, 30%). ¹H NMR (400 MHz, CDCl₃): δ8.37-8.30 (m, 1H), 7.79 (m, 3H), 3.82 (s, 4H), 3.75 (s, 3H), 1.06 (s,6H).

Boronate Ester 35-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-ethyl-1,3-benzoxazol-2(3H)-one

Cesium carbonate (1.79 g, 5.5 mmol) was added to a solution of5-bromo-1,3-benzoxazol-2(3H)-one (1.07 g, 5.0 mmol) in DMF (10 mL).Ethyl iodide (0.44 mL, 5.5 mmol) was added dropwise and the reactionstirred at rt for 24 h. The solvents were removed under reduced pressureand the resultant oil dissolved in EtOAc. The organic extract was washedsequentially with water, saturated sodium chloride solution, dried(magnesium sulfate), filtered and concentrated under reduced pressure.The resultant oil was purified by silica gel column chromatographyeluting with a ratio of 1:2 DCM:iso-hexane to afford the subtitledcompound as a white solid (1.06 g, 88%). ¹H NMR (400 MHz, CDCl₃): δ 7.25(dd, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 3.87 (dd, 2H), 1.39 (t, 3H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-1,3-benzoxazol-2(3H)-one

Bis(neopentyl glycolato)diboron (616 mg, 2.73 mmol) and potassiumacetate (487 mg, 4.96 mmol) were added to a solution of5-bromo-3-ethyl-1,3-benzoxazol-2(3H)-one (600 mg, 2.48 mmol) in1,4-dioxane (10 mL). The reaction mixture was degassed under nitrogenfor 30 min before Pd(dppf)Cl₂.DCM (101 mg, 0.12 mmol) was added. Thereaction mixture was heated at 80° C. for 4 h. After this time thereaction mixture was concentrated under reduced pressure and purified bysilica gel column chromatography eluting with 0-20% EtOAc in iso-hexaneto afford the title compound as an off-white solid (338 mg, 57%). ¹H NMR(400 MHz, CDCl₃): δ 7.60 (d, 1H), 7.41 (s, 1H), 7.19 (d, 1H), 3.90 (dd,2H), 3.79 (s, 4H), 1.43-1.35 (m, 3H), 1.04 (s, 6H).

Boronate Ester 45-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-onei) 5-Chloro-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step i) using5-chloro-7-methyl-1,3-benzoxazol-2(3H)-one (Boronate ester 1 step i) toafford the subtitled compound as a brown solid (258 mg, 82%). ¹H NMR(400 MHz, CDCl₃): δ 6.93 (s, 1H), 6.82 (d, 1H), 3.85 (q, 2H), 2.35 (s,3H), 1.37 (t, 3H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 1 step iii) using5-chloro-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one to afford the titlecompound as an orange solid (285 mg, 81%). ¹H NMR (400 MHz, CDCl₃): δ7.42 (s, 1H), 7.24 (s, 1H), 3.93-3.83 (m, 2H), 3.78 (s, 4H), 2.37 (s,3H), 1.41-1.32 (m, 3H), 1.04 (s, 6H).

Boronate Ester 55-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-(2-oxopropyl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step i) using5-bromo-1,3-benzoxazol-2(3H)-one and chloroacetone to afford thesubtitled compound as a yellow solid (1.31 g, 94%). ¹H NMR (400 MHz,CDCl₃): δ 7.28-7.24 (m, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 4.59 (s, 2H),2.31 (s, 3H).

ii) 5-Bromo-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one

Methyl magnesium chloride (1.62 mL, 4.87 mmol, 3 M solution in THF) wasadded to a solution of 5-bromo-3-(2-oxopropyl)-1,3-benzoxazol-2(3H)-one(1.31 g, 4.87 mmol) in THF (20 mL) at 0° C. with stirring. After 1 hadditional methyl magnesium chloride (0.81 mL, 2.43 mmol) was added. Thereaction was warmed to rt and stirred for 1 h before quenching withammonium chloride (saturated aqueous solution). The reaction mixture wasdiluted with EtOAc and the layers separated. The organic extracts werewashed sequentially with water, saturated sodium chloride solution,dried (magnesium sulphate), filtered and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography eluting with EtOAc and iso-hexane to afford the subtitledcompound as a brown solid (428 mg, 31%). ¹H NMR (400 MHz, CDCl₃): δ 8.26(s, 1H), 7.28-7.23 (m, 1H), 7.16-7.03 (m, 1H), 7.00-6.89 (m, 1H), 3.86(s, 2H), 1.61 (s, 6H).

iii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step ii) using5-bromo-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one to affordthe title compound as an orange solid (269 mg, 56%). ¹H NMR (400 MHz,CDCl₃): δ 8.53 (s, 1H), 7.62 (dd, 1H), 7.42 (d, 1H), 7.06 (d, 1H), 3.96(s, 2H), 3.76 (s, 4H), 1.62 (s, 6H), 1.11-0.96 (m, 6H).

Boronate Ester 65-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-onei) 5-Bromo-7-fluoro-1,3-benzoxazol-2(3H)-one

CDI (2.38 g, 14.70 mmol) was added to a solution of2-amino-4-bromo-6-fluorophenol (2.5 g, 12.25 mmol) in THF (65 mL). Thereaction was heated at reflux for 2.5 h before cooling to rt. Thereaction mixture was transferred to a separating funnel and diluted withEtOAc (100 mL). The mixture was washed sequentially with 2 Mhydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution. The organic extractswere dried (sodium sulfate), filtered and concentrated under reducedpressure. The resultant dark brown solid was triturated with diethylether and iso-hexane to afford the subtitled compound as a light brownsolid (2.01 g, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 7.38(dd, 1H), 7.16-7.15 (m, 1H).

ii) 5-Bromo-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one

A solution of 5-bromo-7-fluoro-1,3-benzoxazol-2(3H)-one (2.01 g, 8.74mmol) in DMF (30 mL) was added dropwise to a suspension of sodiumhydride (419 mg, 10.49 mmol, 60% dispersion in mineral oil) in DMF (50mL) at 0° C. with stirring. The reaction was warmed to rt for 30 minthen re-cooled to 0° C. Methyl iodide (653 μL) was added dropwise andthe reaction allowed to warm to rt. After 18 h the reaction wascautiously quenched with water and transferred to a separating funnel.The mixture was extracted with diethyl ether (×3). The organic extractswere washed sequentially with saturated sodium chloride solution, dried(magnesium sulphate), filtered and concentrated under reduced pressure.The resultant material was triturated with diethyl ether and iso-hexaneto afford the subtitled compound as a light brown solid (1.38 g, 64%).¹H NMR (400 MHz, DMSO-d₆): δ 7.49 (d, 1H), 7.44 (dd, 1H), 3.35 (s, 3H).

iii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one

Bis(neopentyl glycolato)diboron (1.39 g, 6.17 mmol) and potassiumacetate (1.10 g, 11.20 mmol) were added to a solution of5-bromo-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (1.38 g, 5.60 mmol)in 1,4-dioxane (20 mL). The reaction mixture was degassed with nitrogenfor 15 min before Pd(dppf)Cl₂.DCM (229 mg, 0.28 mmol) was added. Thereaction mixture was heated at 80° C. for 3 h. After this time thereaction mixture was concentrated under reduced pressure and purified bysilica gel column chromatography eluting with 20% EtOAc in iso-hexane toafford the title compound as a light brown solid (1.16 g, 75%). ¹H NMR(400 MHz, CDCl₃): δ 7.36 (d, 1H), 7.19 (m, 1H), 3.78 (s, 4H), 3.42 (s,3H), 1.03 (s, 6H).

Boronate Ester 75-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-(2,2-difluoroethyl)-7-fluoro-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step i) using5-bromo-7-fluoro-1,3-benzoxazol-2(3H)-one (Boronate ester 6 step i) and2,2-difluoroethyl trifluoromethane sulfonate to afford the subtitledcompound as a brown solid (2.49 g, 89%). ¹H NMR (400 MHz, CDCl₃): δ 7.16(dd, 1H), 7.05 (s, 1H), 6.08 (tt, 1H), 4.16 (td, 2H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2,2-difluoroethyl-2-methylpropyl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step ii) using5-bromo-3-(2,2-difluoroethyl)-7-fluoro-1,3-benzoxazol-2(3H)-one toafford the title compound as an off-white solid (1.15 g, 41%). ¹H NMR(400 MHz, CDCl₃): δ 7.40 (d, 1H), 7.30-7.24 (m, 1H), 6.10 (tt, 1H),4.23-4.12 (m, 2H), 3.78 (s, 4H), 1.03 (s, 6H).

Boronate Ester 85-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one

2-Dimethylaminoethyl chloride hydrochloride (1.21 g, 8.41 mmol) wasadded to 5-bromo-1,3-benzoxazol-2(3H)-one (1.80 g, 8.41 mmol) andpotassium carbonate (3.87 g, 28.0 mmol) in DMF (10 mL). The reaction washeated at 125° C. for 3.5 h before cooling to rt and pouring ontoice-water. The aqueous layer was extracted with EtOAc (4×100 mL). Thecombined organic extracts were dried (magnesium sulphate), filtered andconcentrated under reduced pressure. The resultant oil was dissolved indiethyl ether, washed with water, dried (magnesium sulphate), filteredand concentrated under reduced pressure to afford the subtitled compoundas a light brown oil (1.63 g, 68%). ¹H NMR (400 MHz, CDCl₃): δ 7.23 (dd,1H), 7.15 (d, 1H), 7.10-7.02 (m, 1H), 3.93-3.85 (m, 2H), 2.69-2.61 (m,2H), 2.30 (s, 6H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step ii) using5-bromo-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one to affordthe title compound as an off-white solid (1.15 g, 41%). Used withoutfurther purification in the next step.

Boronate Ester 96-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-onei) 6-Bromo-3,3-difluoro-1,3-dihydro-2H-indol-2-one

Bis(2-methoxyethyl)aminosulfur trifluoride (deoxo-fluor, 44.25 mL, 22.12mmol, 50% solution in THF) was added dropwise over 30 min to asuspension of 6-bromoisatin (2.0 g, 8.75 mmol) in DCM (90 mL) at rt withstirring. After 24 h the reaction was cautiously quenched with saturatedsodium hydrogen carbonate solution (40 mL) solution at 0° C. The layerswere separated and the organics extracts dried (hydrophobic frit/phaseseparator) and concentrated under reduced pressure. The crude materialwas purified by silica gel column chromatography eluting with 20% EtOAcin iso-hexane to afford the subtitled compound as an orange solid (1.63g, 74%). ¹H NMR (400 MHz, CH₃OH-d₄): δ 7.50-7.46 (m, 1H), 7.36 (dd, 1H),7.18 (d, 1H), (one exchangeable not observed).

ii) 6-Bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one

Prepared according to procedure in Boronate ester 3 step i) using6-bromo-3,3-difluoro-1,3-dihydro-2H-indol-2-one and methyl iodide toafford the subtitled compound as an orange solid (1.39 g, 82%). Usedwithout further purification in the next step.

iii)6-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one

Prepared according to procedure in Boronate ester 3 step ii) using6-bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one to afford thetitle compound as an off-white solid (120 mg, 8%). ¹H NMR (400 MHz,CDCl₃): δ 7.62 (t, 1H), 7.55-7.47 (m, 1H), 7.31-7.28 (m, 1H), 3.80 (s,4H), 3.22 (s, 3H), 1.04 (s, 6H).

Boronate Ester 103-(Cyclopropylmethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-(cyclopropylmethyl)-1,3-benzoxazol-2(3H)-one

Cesium carbonate (1.79 g, 5.5 mmol) was added to a solution of5-bromo-1,3-benzoxazol-2(3H)-one (1.07 g, 5.0 mmol) in DMF (10 mL).(Bromomethyl)cyclopropane (743 mg, 5.5 mmol) was added dropwise and thereaction stirred at rt for 24 h. The solvents were removed under reducedpressure and the resultant oil dissolved in EtOAc. The organic extractwas washed with water, saturated sodium chloride solution, dried(magnesium sulfate), filtered and concentrated under reduced pressure.The resultant oil was purified by silica gel column chromatographyeluting with a 1:2 ratio of DCM:iso-hexane to afford the subtitledcompound as a white solid (918 mg, 68%). ¹H NMR (400 MHz, CDCl₃): δ 7.24(dd, 1H), 7.17 (d, 1H), 7.13-7.04 (m, 1H), 3.68 (d, 2H), 1.29-1.17 (m,1H), 0.69-0.54 (m, 2H), 0.51-0.41 (m, 2H).

ii)3-(Cyclopropylmethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step ii) using5-bromo (cyclopropylmethyl)-1,3-benzoxazol-2(3H)-one to afford the titlecompound as a brown solid (520 mg, 62%). Used without furtherpurification in the next step.

Boronate Ester 115-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-onei) 5-Chloro-3-(2-methoxy ethyl)-1,3-benzothiazol-2 (3H)-one

Prepared according to procedure in Boronate ester 1 step ii) using5-chloro-1,3-benzothiazol-2(3H)-one and 1-bromo-2-methoxyethane toafford the subtitled compound as a yellow solid (3.5 g, 89%). ¹H NMR(400 MHz, CDCl₃): δ 7.32 (d, 1H), 7.22 (d, 1H), 7.13 (dd, 1H), 4.12-4.06(m, 2H), 3.71-3.65 (m, 2H), 3.34 (s, 3H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one

Prepared according to procedure in Boronate ester 1 step iii) using5-chloro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one to afford thetitle compound as a pale brown solid (1.02 g, 64%). Used without furtherpurification in the next step.

Boronate Ester 125-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-isopropyl-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-isopropyl-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step i) using5-bromo-1,3-benzoxazol-2(3H)-one and 2-iodopropane to afford thesubtitled compound as a white solid (510 mg, 66%). Used without furtherpurification in the next step.

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-isopropyl-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step ii) using5-bromo-3-isopropyl-1,3-benzoxazol-2(3H)-one to afford the subtitledcompound as a brown solid (132 mg, 19%). Used without furtherpurification in the next step.

Boronate Ester 136-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-2H-1,4-benzoxazin-3(4H)-one

Prepared according to procedure in Boronate ester 3 step ii) usingcommercially available 6-bromo-4-methyl-2H-1,4-benzoxazin-3(4H)-one toafford the title compound as a brown solid (520 mg, 62%). Usedimmediately without further purification.

Boronate Ester 147-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinolin-2(1H)-one i)7-Bromoquinolin-2(1H)-one

A stirred solution mixture of 7-bromo-2-chloroquinoline (5.0 g, 20.6mmol) in 5 M aqueous hydrochloric acid (133 mL) and 1,4-dioxane (14 mL)was heated at reflux for 2 h. The reaction was cooled and the resultingprecipitate was collected by filtration and washed with water to affordthe subtitled compound as a colourless solid (4.3 g, 93%). ¹H NMR (400MHz, DMSO-d₆): δ 11.80 (s, 1H), 7.91 (d, 1H), 7.63 (d, 1H), 7.48 (d,1H), 7.34 (dd, 1H), 6.53 (d, 1H).

ii) 7-Bromo-1-methylquinolin-2(1H)-one

Sodium hydride (320 mg, 7.98 mmol, 60% dispersion on mineral oil) wasadded to a solution of 7-bromoquinolin-2(1H)-one (1.5 g, 6.64 mmol) inanhydrous THF at rt under an atmosphere of nitrogen with stirring. After1 h the reaction mixture was cooled to 0° C. and methyl iodide (1.88 g,0.81 ml, 13.28 mmol) was added and the reaction was allowed to slowlywarm to rt. After 18 h the reaction was cautiously quenched with water(1 mL) and concentrated under reduced pressure. The resulting residuewas partitioned between EtOAc and water. The layers were separated andthe aqueous layer was extracted with EtOAc. The combined organicextracts were dried (magnesium sulfate), filtered and concentrated underreduced pressure. The residue was recrystallized from DCM by addition ofisohexane to afford the subtitled compound as a colourless solid (650mg, 40%). ¹H NMR (400 MHz, CDCl₃): δ 7.62 (d, 1H), 7.53 (d, 1H), 7.40(s, 1H), 7.35 (dd, 1H), 6.75-6.66 (m, 1H), 3.69 (s, 3H).

ii) 7-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinolin-2(1H)-one

Prepared according to procedure in Boronate ester 2 starting from7-bromo-1-methylquinolin-2(1H)-one to afford the title compound as apale pink solid (650 mg, 88%). ¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 1H),7.69-7.60 (m, 2H), 7.53 (d, 1H), 6.73 (d, 1H), 3.82 (s, 4H), 3.78 (s,3H), 1.05 (s, 6H).

Boronate Ester 155-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one

4-(Chloromethyl)tetrahydro-2H-pyran (500 mg, 3.7 mmol) was added to5-bromo-2-benzoxazolinone (795 mg, 3.7 mmol) and cesium carbonate (500mg, 7.4 mmol) in DMF (10 mL). The reaction was heated at 110° C. for 48h before cooling to rt and pouring onto ice-water. The resultantprecipitate was collected by filtration and dried under vacuum to affordthe subtitled compound as a light brown oil (840 mg, 73%). ¹H NMR (400MHz, DMSO-d₆): δ 7.70 (s, 1H), 7.34-7.27 (m, 2H), 3.88-3.78 (m, 2H),3.71 (d, 2H), 3.25 (td, 2H), 2.11-1.99 (m, 1H), 1.53 (d, 2H), 1.35-1.22(m, 2H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 2 starting from5-bromo-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one toafford the title compound as a orange solid (440 mg, 47%). ¹H NMR (400MHz, CDCl₃): δ 7.61 (dd, 1H), 7.37 (s, 1H), 3.98 (dd, 2H), 3.79 (s, 3H),3.75-3.69 (m, 2H), 3.40-3.32 (m, 2H), 2.25-2.11 (m, 1H), 1.66-1.53 (m,3H), 1.53-1.39 (m, 2H), 1.04 (s, 6H) (one H under CHCl₃ peak).

Boronate Ester 167-Chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-onei) 4-Bromo-2-chloro-6-nitrophenol

70% aqueous nitric acid (11.5 mL, 190 mol) was added slowly to asolution of 4-bromo-2-chlorophenol (20.0 g, 96.4 mmol) in acetic acid(100 mL) at rt. The resultant precipitate was collected by filtration toafford the subtitled compound as a yellow solid (24.0 g). Used withoutfurther purification in the next step.

ii) 2-Amino-4-bromo-6-chlorophenol

Calcium chloride (443 mg, 4 mmol) and iron (11.16 g, 0.2 mol) were addedto a solution of 4-bromo-2-chloro-6-nitrophenol (10.0 g) in ethanol (400mL) and water (100 mL). The suspension was heated at 80° C. for 2 h. Thereaction was cooled, filtered and the filtrate was concentrated underreduced pressure. The resulting residue was diluted with saturatedsodium chloride solution (500 mL) and extracted with EtOAc (2×500 mL).The combined organic extracts were dried (magnesium sulfate), filteredand concentrated under reduced pressure to afford the subtitled compoundas a black solid (4 g, 45%). ¹H NMR (400 MHz, CDCl₃): δ 6.85 (d, 1H),6.75 (d, 1H), 5.38 (s, 1H), 3.92 (bs, 2H).

iii) 5-Bromo-7-chloro-1,3-benzoxazol-2(3H)-one

CDI (4.0 g, 24.6 mmol) was added to a stirred solution of2-amino-4-bromo-6-chlorophenol (2.0 g, 9.0 mmol) in anhydrous THF (50mL). The mixture was heated at reflux for 2.5 h under an atmosphere ofnitrogen. The reaction was allowed to cool and the solvents were removedunder reduced pressure. The resulting residue was washed with 2 Naqueous hydrochloric acid then triturated with methanol to afford thesubtitled compound as a brown solid (0.8 g, 36%). ¹H NMR (400 MHz,DMSO-d₆): δ 12.18 (s, 1H), 7.46 (d, 1H), 7.27 (d, 1H).

iv) 5-Bromo-7-chloro-3-methyl-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 1 step ii) startingfrom 5-bromo-7-chloro-1,3-benzoxazol-2(3H)-one and substituting cesiumcarbonate for potassium carbonate to afford the subtitled compound asbrown solid (700 mg, 83%). ¹H NMR (400 MHz, CDCl₃): δ 7.26 (s, 1H), 7.02(d, 1H), 3.40 (s, 3H).

v)7-Chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 2 starting from5-bromo-7-chloro-3-methyl-1,3-benzoxazol-2(3H)-one to afford the titlecompound as a off-white solid (170 mg, 22%). ¹H NMR (400 MHz, CDCl₃): δ7.59 (s, 1H), 7.28 (s, 1H), 3.78 (s, 4H), 3.41 (s, 3H), 1.03 (s, 6H).

Boronate Ester 173-(2,2-Difluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-onei) 5-Chloro-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-one

Cesium carbonate (3.83 g, 11.8 mmol) was added to a solution of5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL),followed by 2,2-difluoroethyl trifluoromethanesulfonate (1.38 g, 6.5mmol) dropwise and the resulting mixture was stirred at rt for 30 min.After this time water (60 mL) was added and the resulting precipitatewas collected by filtration, washed with water and dried in vacuo toafford the subtitled compound as a white solid (1.25 g, 91%). ¹H NMR(400 MHz, CDCl₃): δ 7.24-7.18 (m, 1H), 7.08 (m, 1H), 7.01 (s, 1H),6.17-5.85 (m, 1H), 4.14-4.04 (m, 2H).

ii) 3-(2,2-Difluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 1 step iii) using5-chloro-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-one to afford thetitle compound as an off-white solid (670 mg, 40%). ¹H NMR (400 MHz,CDCl₃): δ 7.67-7.61 (m, 1H), 7.48 (s, 1H), 7.21 (d, 1H), 6.26-5.93 (m,1H), 4.22-4.10 (m, 2H), 3.78 (s, 4H), 1.03 (s, 6H).

Boronate Ester 183-(2,2,2-Trifluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-onei) 5-Chloro-3-(2,2,2-trifluoroethyl)-1,3-benzoxazol-2(3H)-one

Cesium carbonate (3.83 g, 11.8 mmol) followed by 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.5 g, 6.5 mmol) were added to a solution of5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL). Theresulting mixture was stirred at rt for 30 min. Water (60 mL) was addedand the resulting precipitate was collected by filtration, washed withwater and dried in vacuo to afford the subtitled compound as a whitesolid (1.31 g, 89%). ¹H NMR (400 MHz, CDCl₃): δ 7.19-7.15 (m, 2H), 7.08(s, 1H), 4.40 (q, 2H).

ii)3-(2,2,2-Trifluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 1 step iii) using5-chloro-3-(2,2,2-trifluoroethyl)-1,3-benzoxazol-2(3H)-one to afford thetitle compound as an off-white solid (670 mg, 40%). ¹H NMR (400 MHz,CDCl₃): δ 7.67 (dd, 1H), 7.47 (s, 1H), 7.22 (d, 1H), 4.41 (dd, 2H), 3.78(s, 4H), 1.03 (s, 6H).

Boronate Ester 195-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzothiazol-2(3H)-onei) 5-Chloro-3-methyl-1,3-benzthiazol-2(3H)-one

Cesium carbonate (17.5 g, 53.8 mmol) was added to a solution of5-chloro-1,3-benzothiazol-2(3H)-one (5.0 g, 26.9 mmol) in DMF (70 mL).After 20 min methyl iodide (2.51 mL, 40.4 mmol) was added dropwise. Uponcomplete addition the reaction mixture was stirred at rt for 2 h beforepouring onto ice-water (300 mL). The resultant brown precipitate wascollected by filtration and dried in a vacuum oven to afford thesubtitled compound as a colourless solid (4.42 g, 82%). ¹H NMR (400 MHz,CDCl₃): δ 7.35 (d, 1H), 7.17 (dd, 1H), 7.06 (d, 1H), 3.45 (s, 3H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzothiazol-2(3H)-one

Prepared according to procedure in Boronate ester 1 step iii) using5-chloro-3-methyl-1,3-benzothiazol-2(3H)-one to afford the titlecompound as an off-white solid (620 mg, 15%). ¹H NMR (400 MHz, CDCl₃): δ7.61 (dd, 1H), 7.50-7.36 (m, 2H), 3.80 (s, 4H), 3.48 (s, 3H), 1.04 (s,6H).

Boronate Ester 206-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-2H-1,4-benzothiazin-3(4H)-onei) 2-((4-Bromo-2-nitrophenyl)thio)acetic acid

Potassium carbonate (4.55 g, 33 mmol) and thioacetic acid (1.15 mL, 16.5mmol) were added sequentially to a solution of4-bromo-1-fluoro-2-nitrobenzene (3.02 g, 15 mmol) in DMF (20 mL) withstirring at rt. After 18 h the reaction was diluted with EtOAc andwater. The layers were separated. The aqueous layer acidified andextracted with EtOAc. The organic extract was dried (magnesiumsulphate), filtered and concentrated under reduced pressure to affordthe subtitled compound as a yellow solid (2.60 g, 59%). ¹H NMR (400 MHz,DMSO-d₆): δ 13.04 (s, 1H), 8.37 (d, 1H), 7.96-7.91 (m, 1H), 7.54 (d,1H), 4.05 (s, 2H).

ii) 6-Bromo-2H-1,4-benzothiazin-3(4H)-one

Iron(II) sulfate heptahydrate (18.12 g, 65.17 mmol) in water (25 mL) wasadded slowly to a solution of ammonium hydroxide (26 mL) and2-((4-bromo-2-nitrophenyl)thio)acetic acid (2.6 g, 8.93 mmol) at rt.After 3 h the reaction mixture was filtered through celite washing withammonium hydroxide and water. The filtrate was acidified withconcentrated hydrochloric acid and the resultant precipitate wascollected by filtration. The solid was dissolved in EtOAc, dried(magnesium sulphate), filtered and concentrated under reduced pressureto afford the subtitled compound as a yellow solid (1.9 g, 93%). ¹H NMR(400 MHz, DMSO-d₆): δ 10.64 (br, 1H), 7.36-7.26 (m, 1H), 7.15 (dd, 2H),3.49 (s, 2H).

iii) 6-Bromo-4-methyl-2H-1,4-benzothiazin-3(4H)-one

Prepared according to the procedure in Boronate ester 1 step ii)starting with 6-bromo-2H-1,4-benzothiazin-3(4H)-one to afford thesubtitled compound as a yellow solid (1.16 g, 86%). ¹H NMR (400 MHz,CDCl₃): δ 7.25 (d, 1H), 7.21 (d, 1H), 7.15 (dd, 1H), 3.42 (s, 3H), 3.40(s, 2H).

iv)6-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one

Prepared according to procedure in Boronate ester 3 step ii) using6-bromo-4-methyl-2H-1,4-benzothiazin-3(4H)-one to afford the titlecompound as a white solid (655 mg, 45%). ¹H NMR (400 MHz, CDCl₃): δ7.58-7.44 (m, 1H), 7.45 (dd, 1H), 7.38-7.30 (m, 1H), 3.77 (s, 4H), 3.48(s, 3H), 3.47-3.35 (m, 2H), 1.03 (s, 6H).

Boronate Ester 215-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-onei) 5-Bromo-3-(2-methoxy ethyl)-1,3-benzoxazol-2 (3H)-one

Prepared according to procedure in Boronate ester 3 step i) using5-bromo-1,3-benzoxazol-2(3H)-one to afford the subtitled compound as ayellow solid (1.15 g, 85%). ¹H NMR (400 MHz, CDCl₃): δ 7.27-7.20 (m,2H), 7.06 (d, 1H), 3.97 (t, 2H), 3.72-3.66 (m, 2H), 3.35 (s, 3H).

ii) 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one

Prepared according to procedure in Boronate ester 3 step ii) using5-bromo-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one to afford the titlecompound as a yellow oil. Used without further purification in the nextstep. (1.15 g, 85%).

Boronate Ester 225-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one

i) 5-Chloro-3-methyl-1,3-benzoxazol-2(3H)-one

Cesium carbonate (19.21 g, 58.96 mmol) was added to a solution of5-chloro-1,3-benzoxazol-2(3H)-one (10 g, 58.96 mmol) in DMF (100 mL).After 30 min methyl iodide (4.40 mL, 70.75 mmol) was added dropwise.Upon complete addition the reaction mixture was stirred at rt for 18 hbefore pouring onto ice-water (500 mL). The resultant white precipitatewas collected by filtration and dried in a vacuum oven over P₂O₅ toafford the subtitled compound as a white solid (9.92 g, 92%). ¹H NMR(400 MHz, DMSO-d₆): δ 7.46 (d, 1H), 7.36 (d, 1H), 7.17 (dd, 1H), 3.34(s, 3H).

ii)5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one

Bis(neopentyl glycolato)diboron (5.54 g, 24.5 mmol) and potassiumacetate (3.21 g, 32.7 mmol) were added to a solution of5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (3.0 g, 16.3 mmol) in1,4-dioxane (80 mL). The reaction mixture was degassed under nitrogenfor 40 min before XPhos (311 mg, 0.65 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos-Pd-G2, 257 mg, 0.33 mmol) were added. The reaction mixture washeated at 80° C. for 2 h. After this time the reaction mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography eluting with 0-10% EtOAc in iso-hexane to afford thetitle compound as a yellow solid (4.8 mg, >100%). ¹H NMR (400 MHz,CDCl₃): δ 7.61 (dd, 1H), 7.40 (s, 1H), 7.21-7.13 (m, 1H), 3.79 (s, 4H),3.41 (s, 3H), 1.04 (s, 6H).

Preparation of Intermediate Building Blocks Intermediate 14′-[(2S)-2-Amino-2-cyanoethyl]biphenyl-4-carbonitrile i) tert-Butyl[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamate

Potassium carbonate (4.5 g, 36 mmol) was added to a suspension oftert-butyl N-[(1S) cyano-2-(4-iodophenyl)ethyl]carbamate (preparedaccording to the procedure in WO2009/74829, p 47), (5.99 g, 16 mmol) and(4-cyanophenyl)boronic acid (2.64 g, 18 mmol) in 1,4-dioxane (60 mL) andwater (8 mL). The suspension was stirred under a stream of nitrogen for15 min before Pd(dppf)Cl₂.DCM (1.3 g) was added. The reaction was heatedat 75° C. for 45 min before concentrating under reduced pressure. Theresultant oil was diluted with EtOAc (200 mL), washed with water (100mL) and saturated sodium chloride solution (50 mL). The organic extractswere dried (magnesium sulfate), filtered and evaporated under reducedpressure to afford a brown oil. The oil was purified by silica gelcolumn chromatography eluting with 20-30% EtOAc in iso-hexane to affordthe subtitled compound as a colourless solid (5.9 g, 90%). ¹H NMR (400MHz, DMSO-d₆): δ 10.63 (s, 1H), 7.96-7.81 (m, 4H), 7.73 (d, 2H), 7.45(d, 2H), 4.71 (q, 1H), 3.18-3.05 (m, 2H), 1.36 (s, 9H).

ii) 4′-[(2,5)-2-Amino-2-cyanoethyl]biphenyl-4-carbonitrile

tert-Butyl [(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamate (5.4g, 15.5 mmol) was dissolved in formic acid (50 mL) and heated to 50° C.for 15 min on a pre-heated stirrer hotplate. The solution was evaporatedunder reduced pressure and diluted with EtOAc (150 mL). Saturatedaqueous solution of sodium bicarbonate solution was added until themixture was basic (pH 8). The EtOAc was separated and washed withsaturated sodium chloride, dried (magnesium sulfate), filtered andevaporated under reduced pressure to give a yellow oil. The oil waspurified by silica gel column chromatography eluting with EtOAc toafford the title compound as a colourless solid (2.88 g, 74%). ¹H NMR(400 MHz, CDCl₃): δ 7.62 (m, 4H), 7.52 (m, 2H), 7.35 (d, 2H), 3.92 (t,1H), 3.10-2.96 (m, 2H) (two exchangeable protons not observed).

Intermediate 2(2S)-2-Amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrilei) tert-Butyl{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamate

5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one(Boronate ester 22, 3.34 g, 12.81 mmol) and (S)-tert-butyl(1-cyano-2-(4-iodophenyl)ethyl)carbamate (prepared according to theprocedure in WO 2009/074829, p. 47), 12.81 mmol were dissolved in1,4-dioxane (340 mL) and water (12 mL). The reaction mixture wasdegassed under nitrogen for 30 min before potassium carbonate (2.66 g,19.21 mmol) and Pd(dppf)Cl₂.DCM (1.05 g, 1.28 mmol) were added. Thereaction mixture was heated at 80° C. for 1.5 h. After this time thereaction was concentrated under reduced pressure. The residue wasdiluted with EtOAc (200 mL) and water (50 mL). The mixture was filteredthrough celite and the layers separated. The organic extracts werewashed with saturated sodium chloride solution, dried (magnesiumsulphate), filtered and evaporated. The resultant oil was purified bysilica gel column chromatography eluting with a gradient of 0-40% EtOAcin iso-hexane to afford the subtitled compound as a white solid (3.87mg, 77%). ¹H NMR (400 MHz, CDCl₃): δ 7.51-7.46 (m, 2H), 7.31 (d, 2H),7.21-7.17 (m, 3H), 7.12-7.06 (m, 1H), 4.78 (s, 1H), 3.39 (s, 3H),3.14-2.98 (m, 2H), 1.39 (s, 9H).

ii)(2S)-2-Amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile

Formic acid (32 mL) was added to tert-butyl{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamate(3.87 g, 9.84 mmol). The mixture was heated at 50° C. for 15 min on apre-heated stirrer hotplate. After this time the solvents were removedunder reduced pressure. The residue was dissolved in DCM, washed withsaturated hydrogen carbonate solution, dried (phase separatingcartridge) and concentrated under reduced pressure. The crude materialwas purified by silica gel column chromatography eluting with 80-100%EtOAc in iso-hexane to afford the title compound as a white solid (1.76g, 59%). ¹H NMR (400 MHz, CDCl₃): δ 7.60-7.50 (m, 2H), 7.39 (d, 2H),7.34-7.30 (m, 1H), 7.25 (t, 1H), 7.14 (d, 1H), 4.02-3.96 (m, 1H), 3.45(s, 3H), 3.18-3.01 (m, 2H), 1.67 (s, 2H).

Intermediate 3 (2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylicacid

i) 3-{Benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol

A solution of N-benzylpropanolamine (3.3 g) and benzyl(S)-(+)-glycidylether (3.6 g) in ethanol (40 mL) was heated at 40° C. for 18 h. Thesolvent was evaporated under reduced pressure to give the subtitledcompound as a colourless oil (6.8 g, 100%), which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 7.29 (m, 10H), 4.54(m, 1H), 4.45 (s, 2H), 4.36 (t, 2H), 3.76 (m, 1H), 3.44 (m, 5H), 2.47(m, 4H), 1.57 (m, 2H).

ii) (2S)-4-Benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane

Sodium hydride (15.2 g, 0.38 mol, 60% dispersion in oil) was addedportion-wise to a stirred solution of3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (50.0 g,0.153 mol) in THF (2.5 L) at 0° C. The reaction was stirred at 0° C. for30 min before the portion-wise addition of p-toluenesulphonyl imidazole(37.8 g, 0.17 mol). The reaction was allowed to warm to rt and stirredfor 4 h before cooling to 0° C. The reaction was quenched by the carefuladdition of saturated sodium hydrogen carbonate solution (70 mL). Thesolvents were removed under reduced pressure and the crude residue waspartitioned between water (400 mL) and EtOAc (400 mL). The layers wereseparated and the aqueous portion was extracted with EtOAc (2×400 mL).The combined organic extracts were dried (magnesium sulfate), filteredand evaporated under reduced pressure to give an oil. The oil waspurified by silica gel column chromatography eluting with a gradient of0-50% EtOAc in iso-hexane to afford the subtitled compound as acolourless oil (12.2 g, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.36-7.20 (m,10H), 4.45-4.35 (m, 2H), 3.81-3.65 (m, 2H), 3.60-3.39 (m, 2H), 3.42-3.31(m, 2H), 3.25 (dd, 1H), 2.86 (d, 1H), 2.78-2.70 (m, 1H), 2.54-2.46 (m,1H) 2.37 (dd, 1H), 1.89-1.77 (m, 1H), 1.78-1.66 (m, 1H).

iii) tert-Butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

Di-tert-butyl dicarbonate (10.22 g, 47.1 mmol) and 20% palladium oncarbon (16.5 g) were added to a solution of(2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane (12.2 g, 39.2 mmol) inethanol (250 mL) under nitrogen. The reaction mixture was shaken underan atmosphere of hydrogen at 50 psi for 18 h. After this time thereaction mixture was filtered through celite and washing with methanol.The solvent was evaporated under reduced pressure to give the subtitledcompound as a colourless oil (11.16 g). ¹H NMR (400 MHz, DMSO-d₆): δ4.72-4.66 (m, 1H), 4.00-3.89 (m, 1H), 3.80-3.61 (m, 1H), 3.60-3.47 (m,2H), 3.49-3.21 (m, 4H), 3.07-2.88 (m, 1H), 1.79-1.69 (m, 2H), 1.40 (s,9H).

iv) (2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid

Sodium bromide (1.46 g) and TEMPO (218 mg) were added to a solution oftert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (13.2 g,46.6 mmol) in acetone (730 mL) and saturated sodium hydrogen carbonate(218 mL) at 0° C. 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (23.9 g,102.5 mmol) was added portion-wise and the reaction mixture allowed towarm to rt over 18 h. The reaction was quenched by the addition ofiso-propanol (30 mL) and stirred for 30 min. The reaction mixture wasfiltered through celite, washing with EtOAc. The filtrate was evaporatedunder reduced pressure, dissolved in 1 M sodium carbonate solution (100mL) and extracted with EtOAc (2×200 mL). The aqueous solution wasacidified with 2M HCl (150 mL) and extracted with EtOAc (3×400 mL). Thecombined organic extracts were dried (magnesium sulfate), filtered andevaporated under reduced pressure to give the title compound as acolourless solid (7.86 g, 68%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.71 (s,1H), 4.22-4.15 (m, 1H), 3.98-3.80 (m, 2H), 3.70-3.50 (m, 2H), 3.45-3.11(m, 1H), 3.21-3.06 (m, 1H), 1.71 (s, 2H), 1.40 (d, 9H).

Intermediate 3 (1^(st) Alternative Synthesis)(2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid i) Methyl(2S)-3-(dibenzylamino)-2-hydroxypropanoate

Under an atmosphere of nitrogen, (S)-methyl oxirane-2-carboxylate (117g, 1134 mmol) and dibenzylamine (226 g, 1123 mmol) were heated at 70° C.over night.

More (S)-methyl oxirane-2-carboxylate (1.15 g, 11.2 mmol) was added.Further stirred at 80° C. for 5 h. The mixture was then put underreduced pressure (0-10 mbar) over night at 50° C. This furnished thedesired product as a pale brown viscous oil (342.7 g, 1145 mmol). Assayby ¹H NMR=89% w/w, effective yield 91%.

¹H NMR (400 MHz, CDCl₃): δ 2.77-2.92 (m, 2H), 3.13-3.4 (s, broad, 1H),3.49 (d, J=13.5, 2H), 3.63 (s, 3H), 3.74 (d, J=13.5, 2H), 4.21 (dd,J=4.3, 6.7, 1H), 7.18-7.34 (m, 10H).

ii) Methyl3-{[(2S)-3-(dibenzylamino)-1-methoxy-1-oxopropan-2-yl]oxy}-2-enoate

Methyl (2S)-3-(dibenzylamino)-2-hydroxypropanoate (342.7 g, 1018.8 mmol)was dissolved in toluene (200 mL). 4-methylmorpholine (22.4 mL, 203.8mmol) was added followed by slow addition of methyl propiolate (108.8 g,1273.6 mmol) during 60 min. The reaction temperature was kept in theinterval 20-25° C. during this addition by cooling in a water/ice bath.After 3 h of stirring, the mixture was concentrated to give the desiredproduct as a brown viscous oil (447.6 g, 1167 mmol, mixture of Z/Eisomers). Assay by ¹H NMR=87% w/w, (including both the Z and the Eisomer).

¹H NMR (400 MHz, CDCl₃): δ 2.9-3.02 (m, 2H), 3.53 (d, 2H), 3.64 (s, 3H),3.66 (s, 2H), 3.70 (d, 2H), 4.41 (td, 1H), 4.86 (d, 0.08H), 5.20 (d,0.92H), 6.33 (d, 0.08H), 7.16-7.34 (m, 11H), 7.43 (d, 0.92H).

¹³C NMR (101 MHz, CDCl₃): δ 51.13 (s), 52.30 (s), 54.64 (s), 58.92 (d,J=5.6 Hz), 79.19 (s), 82.16 (s), 97.20 (s), 98.20 (s), 127.14 (s),128.18 (d, J=8.0 Hz), 128.88 (s), 138.54 (s), 138.88 (s), 156.76 (s),161.01 (s), 167.59 (s), 169.04 (s).

iii) Methyl (2S)-3-amino-2-(3-methoxy-3-oxopropoxy)propanoate

Pd(OH)₂, 20% on charcoal, 50% water (11.17 g, 79.50 mmol) was driedunder a stream of nitrogen over night. This was then suspended in1,4-dioxane (200 mL) and then added to a solution of methyl3-{[(2S)-3-(dibenzylamino)-1-methoxy-1-oxopropan-2-yl]oxy}prop-2-enoate(438 g, 994 mmol) dissolved in 1,4-dioxane (3800 mL). The mixture washydrogenated under 10 bar pressure of hydrogen at 30° C. over night. Thetemperature was increased to 40° C. and the mixture was allowed to stirfor another 2 days. The mixture was filtered and rinsed with dioxane(200 mL). The dioxane solution (4527 g) was then used as such in thenext step. Assay=4.6% w/w, effective yield 103%.

¹H NMR (400 MHz, CDCl₃): δ 1.4 (s, 2H), 2.55-2.73 (m, 2H), 2.90-2.97(dd, J=6.7, 13.5, 1H), 3.00-3.08 (dd, J=3.8, 13.5, 1H), 3.69 (s, 3H)3.72-3.74 (m, 1H), 3.75 (s, 3H), 3.87-3.98 (ddd, 3.7, 6.3, 13.5, 2H).

iv) Methyl (2S)-5-oxo-1,4-oxazepane-2-carboxylate

To a crude solution of methyl(2S)-3-amino-2-(3-methoxy-3-oxopropoxy)propanoate (204 g, 994 mmol) indioxane (4.2 L) was added Novozyme 435 (immobilized, 75 g). The mixturewas stirred for 2 days at 45° C. More Novozyme 435 (immobilized, 25 g)was added and the mixture was allowed to stir for another 2 days. Thetemperature was increased to 55° C. and the mixture was allowed to stirfor 24 h. The mixture was filtered through a celite filter and rinsedwith MeOH followed by concentration to a soap-like solid (254 g). Thiswas further purified through preparative HPLC to give 85.2 g (492 mmol)of the desired product as a colorless solid (>90% w/w by ¹H NMR). ¹H NMR(400 MHz, CDCl₃): δ 6.98, (1H, s), 4.19 (2H, m), 3.77 (3H,$), 3.69 (1H,m), 3.59 (2H, m), 2.83 (1H, ddd) and 2.63 (1H, dd).

v) 4-tert-Butyl 2-methyl (2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylate

To a mixture of methyl (2S)-5-oxo-1,4-oxazepane-2-carboxylate (152.5 g,863.0 mmol), dimethylpyridin-4-amine (2.11 g, 17.3 mmol) and THF (1200mL) was added di-tert-butyl dicarbonate (192 g, 863.0 mmol). Theresulting yellow suspension was then stirred at 30° C. for 20 h. Moredi-tert-butyl dicarbonate (11.30 g, 51.8 mmol) was added and the mixturewas stirred at 30° C. for an additional 20 h. The mixture wasconcentrated to almost dryness on a 37° C. water bath. MTBE (400 mL) wasadded followed by concentration to almost dryness. This procedure wasrepeated once in order to remove t-BuOH formed in the reaction. Last,THF (300 mL) was added followed by concentration to a yellow oil that isused directly in the next step. Yield is assumed to be quantitative. ¹HNMR (400 MHz, CDCl₃): δ 1.48 (s, 9H); 2.77 (ddd, 1H, J=16.1, 7.0, 1.9Hz); 2.94 (ddd, 1H, J=16.1, 9.3, 2.5 Hz); 3.75 (s, 3H); 3.80 (ddd, 1H,J=12.9, 9.1, 2.0 Hz); 3.91 (dd, 1H, J=16.0, 7.2 Hz); 4.12-4.30 (m, 2H);4.38 (dd, 1H, J=16.0, 1.4 Hz). ¹³C NMR (126 MHz, CDCl₃): δ 27.9, 42.3,48.8, 52.6, 63.4, 77.5, 83.8, 152.1, 169.0, 172.6.

vi) 4-tert-Butyl 2-methyl (2S)-1,4-oxazepane-2,4-dicarboxylate

To the crude mixture of 4-tert-butyl 2-methyl(2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylate (212.4 g, 777.2 mmol) in THF(2 L) from the previous step was during 30 minutes added a solution ofBH₃-DMS (118 g, 1554 mmol). The reaction temperature was kept in theinterval 20-23° C. during this addition. The mixture was then stirred at23° C. for 17 h. The mixture was now slowly transferred to a solution ofMeOH (1.5 L). The mixture was then combined with crude material obtainedin a small scale experiment (starting from 23.6 g of 4-tert-butyl2-methyl (2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylate using the procedureas described above). The homogenous clear solution was then stirred at20° C. for 1 h followed by concentration to almost dryness. MeOH (500mL) was added followed by concentration to almost dryness, repeatedonce. ACN (500 mL) was then added followed by concentration to almostdryness, repeated once. The crude product (24% w/w, determined by ¹HNMR, benzylbenzoate as internal standard) is then stored as a solutionin ACN (500 mL). Effective yield=71%.

¹H NMR (400 MHz, MeOD, ˜50:50 mixture of rotamers): δ 1.51 (s, 9H);1.84-1.93 (m, 2H); 3.20-3.34 (m, 1H); 3.42-3.56 (m, 1H); 3.70-3.81 (m,5H); 4.02-4.12 (m, 2H); 4.36-4.41 (m, 1H). ¹³C NMR (100.6 MHz, MeOD,˜50:50 mixture of rotamers) δ 28.6, 31.0, 31.5, 47.8, 48.2, 51.0, 51.2,52.6, 68.6, 68.7, 77.6, 77.8, 81.4, 81.6, 156.7, 156.9, 172.8, 172.9.

vii) (2S)-4-(tert-Butoxy carbonyl)-1,4-oxazepane-2-carboxylic acid

LiBr (375 g, 4319 mmol) was added to a mixture of ACN (700 mL), water(30 mL), TEA (187 g, 1851 mmol) and water (30 mL). With a reactiontemperature of 30° C., 4-tert-butyl 2-methyl(2S)-1,4-oxazepane-2,4-dicarboxylate (160 g, 617 mmol) dissolved in ACN(200 mL) was then added. The mixture was stirred vigorously at 20° C.over night.

Most of the ACN was removed through concentration. To the residue wasadded MTBE (500 mL). The yellow aqueous layer was washed with MTBE (200mL). To the aqueous layer was then added MTBE (400 mL) followed byacidification to pH ˜2 using 2M KHSO₄ solution. The aqueous layer wasextracted with MTBE (2×300 mL) and the pooled organic layer was washedwith water (100 mL) followed by concentration to a colorless solid (170g, 80% w/w). The solid was suspended in 30% MTBE in heptane (600 mL) andthe mixture was then stirred over night.

The mixture was filtered and the solid was washed with 25% MTBE inheptane (100 mL) followed by drying under reduced pressure at 40° C.This furnished 140.1 g (571 mmol) of the desired product, 93% w/w by ¹HNMR, 99.7% ee by HPLC.

¹H NMR (400 MHz, MeOD, mixture of 2 rotamers): δ 1.46 (s, 9H); 1.77-1.90(m, 2H); 3.15-3.77 (m, 4H); 3.91-4.17 (m, 2H); 4.22-4.32 (m, 1H). ¹³CNMR (100.6 MHz, MeOD, mixture of 2 rotamers) δ 28.5, 28.6, 31.0, 31.3,47.8, 47.9, 51.4, 68.6, 69.0, 77.7, 78.0, 81.4, 81.7, 156.8, 157.0,174.0, 174.2.

Intermediate 3 (2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylicacid (2^(nd) Alternative Synthesis) i)3-{Benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol

The reactants 3-(benzylamino)propan-1-ol, 1219 g (7.16 mol) and(S)-2-((benzyloxy)methyl)oxirane, 1200 g (7.16 mol) were dissolvedseparately, in 2×3 L of 2-propanol and were charged separately to aninerted reactor and heated at 50° C. for 24 h. The reaction mixture wasevaporated at 60° C., 110 mbar to an oil, 2.48 kg. The oil was dissolvedin toluene, 1 L and evaporated to dryness. Yield: 2.45 kg Assay: ˜95%Effective yield: ˜98%.

¹H NMR (400 MHz, CDCl₃): δ 1.59-1.78 (m, 2H), 2.47 (dd, J=13.3, 1H),2.53-2.65 (m, 2H), 2.71-2.78 (ddd, 5.6, 7.7, 13.2, 1H), 3.31-3.45 (m,3H), 3.50 (d, 1H), 3.67-3.74 (m, J=13.3, 3H), 3.93-3.99 (ddt, J=4.1,4.1, 6.2, 8.3, 1H), 4.48 (s, 2H), 7.18-7.36 (m, 10H).

ii) 3-{Benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propylmethanesulfonate

The diol product from previous experiment, 147 g (446 mmol), wasdissolved in 400 mL of DCM and cooled to −1° C. DIPEA, 72.3 mL (446mmol) was added to the reactor at −1° C. The solution was cooled to −6°C. Then methane sulfonylchloride 51.1 g (446 mmol) in 200 mL of DCM wasadded dropvise to the diol solution at appr. −6° C. to −2° C. during 1h. After addition the mixture was stirred for 30 min, before it waspoured onto 400 mL of ice. Phase separation, wash with cold water twice,followed by brine, twice, evaporated to an oil. The oil was diluted withDCM and extracted with aq. sodium sulfate solution, filtered andevaporated to an oil, 176 g (97%), assay 85%.

¹H NMR (600 MHz, CDCl₃): δ 1.82-1.87 (m, 2H), 2.47-2.56 (m, 3H),2.59-2.67 (m, 1H), 2.86 (s, 3H), 3.02 (s, 1H), 3.38-3.45 (m, 2H), 3.49(d, 1H), 3.69 (d, 1H), 3.83-3.87 (m, 1H), 4.14-4.20 (m, 2H), 4.49 (s,2H), 7.20-7.32 (m, 10H).

iii) (2S)-4-Benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane

The crude product from previous experiment, 169 g (approx assay 85%,143.65 g, 0.35 mol) was dissolved in 300 mL dry THF and was added slowly(5 h) to NaH (1.4 eq., 18.46 g, 0.423 mol) in 200 mL of dry THF in a dryreactor under nitrogen at 25° C. (the sodium hydride paste was washedwith heptane before the addition started). The reaction mixture wasstirred over night at 25° C. The next day 400 mL of saturated ag.bicarbonate was added to the reaction mixture at rt. Initially gas wasevolved. Phase separation, the water phase was discarded. The organicphase was evaporated to an oil. The oil was dissolved in 400 mL ofisopropyl acetate. The isopropyl acetate solution was washed with 2 MNaOH (aq), 100 ml, followed by two washes with water (100 ml) and abrine wash. Evaporation gave 136 g, assay 65% w/w product. Estimatedyield: 88 g (81%) 0.28 mol.

Chromatography: EtOAc/heptane 254 nm.

Isolated yield: 81.6 g (0.26 mol, 74%)

¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.76 (m, 1H), 1.77-1.87 (m, 1H), 2.37(dd, 1H), 2.46-2.5 (m, 1H), 2.68-2.77 (m, 1H), 2.81-2.89 (m, 1H), 3.24(dd, 1H), 3.37 (dd, 1H), 3.64 (d, 2H), 3.64-3.74 (m, 1H), 3.76 (ddd,2H), 4.35-4.43 (m, 2H), 7.18-7.37 (m, 10H).

iv) (2S)-1,4-Oxazepan-2-ylmethanol

The product from previous experiment, 81.6 g (0.26 mol) was dissolved inmethanol, 1 L and charged to the hydrogenation vessel under nitrogen.The catalyst, PdOH₂ (20%) 50% wet on charcoal, 10 g=3 mol % was slurriedin ethanol and charged to the reaction vessel under nitrogen. Themixture was hydrogenated at 4.5 bars at ambient temperature for 72 h.Conversion was approx 50% and 10 g of new catalyst was added andpressure was raised to 8 bars, temperature was increased from ambient to45° C. Hydrogenation over night. Conversion was aprox 96%. 3 g ofcatalyst was added to the reaction mixture and the hydrogenation wascontinued for 6 h. Full conversion was reached and the reaction mixturewas filtered and a sample of it was evaporated to give an oil.

¹H NMR (500 MHz, MeOD): δ 1.60-1.79 (m, 2H), 2.42-2.53 (dd, J=8.8, 14,1H), 2.62-2.81 (dddd, J=4.2, 7.3, 13.5, 49, 2H), 2.81-2.89 (dd, 1H),2.94 (dd, 1H), 3.17 (s, 1H), 3.24-3.37 (qd, J=5.6, 11.4, 11.4, 11.4,2H), 3.41-3.48 (m, 1H), 3.53 (td, J=3.9, 7.9, 7.8, 1H), 3.74-3.84 (dt,J=5.5, 5.5, 12.2, 1H).

v) tert-Butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

The product from previous experiment (approx 0.26 mol) in it's methanolsolution approx 1.2 L after filtration of catalyst was treated with 54.3g (0.25 mol) of Boc-anhydride at rt. CO₂ (g) started to form directly.The reaction was left over night with stirring under nitrogen. Thereaction mixture was evaporated to dryness to give a light yellowliquid, 59 g (98%).

¹H NMR (500 MHz, MeOD): δ 1.47 (s, 9H), 1.81-1.93 (qt, J=3.51, 3.51,6.3, 6.3, 6.3, 2H), 3.03-3.16 (ddd, J=9.5, 14.4, 21.8, 1H), 3.29-3.32(dt, J=1.6, 1.6, 3.3, 1H), 3.32-3.41 (m, 1H), 3.43-3.56 (m, 3H),3.56-3.71 (m, 2H), 3.78 (dd, 1H), 4.07 (tq, 1H).

vi) (2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid

tert-Butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate, 52.5 g(assay 85%, 40.7 g) was dissolved in 300 mL of DCM. TEMPO, 0.5 g wasdissolved 100 mL of DCM, Tertrabutylammonium hydrogensulfate, 3.88 g wasdissolved in 100 mL of DCM. The three DCM solutions were charged to areactor and 100 mL of water was added. 350 mL of sodium hypochloritesolution, 10-15%, was pH adjusted with sodium hydrogen carbonate(liquid+solids) (approx 100 ml) to pH of approx 8-9. 58 mL of sodiumbromide, 0.5 M solution, was added to the above buffered solution. Theresulting water solution was added dropwise at 0° C. to the two-phasesystem consisting of the mixed DCM solutions and water, with highstirring. The reaction generated heat. The addition could be followed bya color change (yellow to pale yellow) that indicated when the oxidantwas consumed. After 10 min the jacket was set to −5° C. to keep theinner temperature at aprox. 10° C. Addition was completed in 45 min andthe reaction mixture was left over night. Work up: At rt, the off whitereaction mixture was pH adjusted to aprox 2-3 with potassiumhydrogensulfate, approx 40 g and the phases were separated, water phasewas washed with DCM, 3×100 ml. The resulting DCM (800 ml) solution wasevaporated to an oil, approx 100 g. The oil was dissolved in bicarbonatesolution, 400 ml, and was extracted with DCM, 2×75 ml. The residualwater phase was acidified to pH 2-3 with potassium hydrogen sulfate,approx 35-40 g, and was extracted with DCM (5×75 ml). The DCM wasevaporated to give 40.7 g of white crystals; yield: 40.7 g, 85% yieldbased on the assay of the starting material. Product contained 10%water.

Purification: product was slurried in 200 mL of toluene and heated to60° C. where it went in to solution. Approx 100 mL of toluene wasevaporated off and the acid product started to crystallize at 60° C. Themixture was cooled to rt. Product was filtered off and was washed withtoluene. Product was dried under reduced pressure.

¹H NMR (600 MHz, CDCl₃): δ 1.46 (s, 9H), 1.93 (s, 2H), 3.23 (ddt, 1H),3.33-3.78 (m, 3H), 3.95-4.38 (m, 3H), 9.91 (s, 1H).

Intermediate 4 tert-Butyl(2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate

(2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid(Intermediate 3, 7.9 g, 32.2 mmol) and (S)-2-amino-3-(4-iodophenyl)propanamide (9.0 g, 32.2 mmol, prepared according to the procedure in WO2009/074829, p. 45) were added to T3P (25 g, 39.3 mmol, 50% solution inDMF) in DMF (200 mL). TEA (25 mL, 180.3 mmol) was added and the reactionwas stirred at rt for 4 h. After this time the reaction mixture wasconcentrated under reduced pressure. The resultant oil was dissolved inEtOAc and washed successively with 2 M aqueous hydrochloric acid,saturated aqueous solution of sodium hydrogen carbonate and sodiumchloride solution. The organic extracts were dried (magnesium sulfate),filtered and concentrated under reduced pressure to afford the titlecompound as a foaming yellow oil (13.1 g, 79%) which was used withoutfurther purification.

Intermediate 5 tert-Butyl(2S)-2-{[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

Burgess reagent (8.16 g, 34.27 mmol) was added to a solution oftert-butyl(2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate(Intermediate 4, 8.86 g, 17.13 mmol) in DCM (740 mL). The reactionmixture was stirred at rt for 24 h after which time the reaction wastransferred to a separating funnel and washed with water. The organicextracts were dried (phase separator cartridge) and concentrated underreduced pressure. The resultant solid was purified by silica gel columnchromatography eluting with 25% EtOAc in iso-hexane to afford a yellowoil. Trituration with diethyl ether afforded the title compound as anoff-white solid (6.05 g, 71%). ¹H NMR (400 MHz, CDCl₃): δ 7.66 (d, 2H),6.98 (m, 3H), 5.06 (s, 1H), 4.22-3.92 (m, 3H), 3.70 (m, 0.5H), 3.54-3.20(m, 2.5H), 3.09-2.89 (m, 3H), 1.88 (s, 2H), 1.42 (s, 9H).

Intermediate 6 tert-Butyl(2S)-2-[[(1S)-2-amino-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]carbamoyl]-1,4-oxazepane-4-carboxylate

Pin₂B₂ (0.32 g, 1.26 mmol), potassium acetate (0.28 g, 2.9 mmol) andPd(dppf)Cl₂.DCM (0.039 g, 5 mol %) were added to a stirred solution oftert-butyl(2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate(Intermediate 4, 0.5 g, 0.97 mmol) in dry DMSO (2.5 mL) under nitrogen.The reaction was heated at 85° C. for 5 h and allowed to stand at rtovernight. Water (15 mL) was added and the mixture was extracted withEtOAc (2×50 mL). The combined extracts were washed with saturated sodiumchloride (20 mL), dried (magnesium sulfate) and evaporated under reducedpressure. The resulting oil was purified by silica gel columnchromatography eluting with EtOAc to give the title compound (0.3 g,60%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, 2H),7.28-7.21 (m, 2H), 5.30 (s, 1H), 4.60 (m, 1H), 4.18-3.98 (m, 2H),3.51-3.42 (m, 1H), 3.12 (t, 2H), 2.80 (s, 1H), 2.05 (s, 2H), 1.88 (s,1H), 1.60 (s, 4H), 1.54-1.33 (m, 6H), 1.40-1.16 (m, 12H) (threeexchangeable protons not observed).

EXAMPLES Example 1(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide

i) tert-Butyl(2S)-2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

2-Pyridinol-1-oxide (0.155 g, 1.4 mmol), TEA (0.36 g, 3.6 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.268 g,1.4 mmol) were added to a solution of(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid(Intermediate 3, 0.294 g, 1.2 mmol) in DCM (15 mL). After 20 min4′-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile (Intermediate 1,0.296 g, 1.2 mmol) was added and the mixture was stirred for 3 h andallowed to stand at rt for 18 h. The mixture was heated at 40° C. for 4h before water (15 mL) was added. After 10 min the DCM was dried (phaseseparating cartridge) and evaporated under reduced pressure. Theresultant yellow oil was purified by silica gel column chromatography togive the subtitled compound (0.29 g, 52%). Used without furtherpurification in the next step.

ii)(2S)—N-[(2S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide

Prepared according to procedure in Method A step ii) using tert-butyl(2S)-2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylateto afford the title compound as a white solid (60 mg, 28%).

¹H NMR (400 MHz, CDCl₃): δ 7.77-7.65 (m, 4H), 7.62-7.57 (m, 2H), 7.40(d, 2H), 7.11 (d, 1H), 5.18-5.11 (m, 1H), 4.19-4.14 (m, 1H), 4.06-3.96(m, 2H), 3.75-3.69 (m, 1H), 3.56-3.48 (m, 2H), 3.18-3.05 (m, 3H),2.95-2.90 (m, 1H), 2.70 (ddd, 1H) (1 exchangeable proton not observed).

LCMS (10 cm_ESCI_Formic_MeCN) t_(R) 2.57 (min) m/z 375 (MH⁺).

Example 2(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

i) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (468 mg,2.44 mmol) and 2-pyridinol 1-oxide (271 mg, 2.44 mmol) were added to asolution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid(Intermediate 3, 490 mg, 2.0 mmol) in DCM (15 mL). The reaction wasstirred at rt for 30 min before the addition of(2S)-2-amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile(Intermediate 2, 586 mg, 2.0 mmol) and DiPEA (1.79 mL, 10 mmol). Thereaction was stirred at rt for 18 h before transferring to a separatingfunnel. The mixture was washed with 2 M hydrochloric acid, saturatedsodium hydrogen carbonate solution and brine. The organic extract wasrun through a hydrophobic frit/phase separator and concentrated underreduced pressure. The crude material was purified by silica gel columnchromatography eluting with 0-60% EtOAc in iso-hexane to afford thesubtitled compound as an oil (457 mg, 44%). ¹H NMR (400 MHz, CDCl₃): δ7.63-7.52 (m, 2H), 7.38 (d, 2H), 7.36-7.24 (m, 2H), 7.35-6.98 (m, 2H),5.18 (t, 1H), 4.22-3.97 (m, 2H), 3.76-3.67 (m, 0.5H), 4.10-2.94 (m,4.5H), 3.35-3.26 (m, 1H), 3.24-3.04 (m, 3H), 2.06-1.82 (m, 2H), 1.47 (s,10H).

ii)(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate(457 mg, 0.85 mmol) was dissolved in formic acid (3 mL) and heated at50° C. for 10 min on a pre-heated stirrer hotplate. After this time thereaction was concentrated under reduced pressure, dissolved in DCM andwashed with saturated sodium hydrogen carbonate solution. The organicextract was run through a hydrophobic frit/phase separator andconcentrated under reduced pressure. The resultant foam was purified bysilica gel column chromatography eluting with 0-5% methanolic ammonia (7N) in DCM to afford the title compound as solid material (230 mg, 64%).

¹H NMR (400 MHz, CDCl₃): δ 7.59-7.51 (m, 2H), 7.39 (dd, 2H), 7.33-7.23(m, 3H), 7.14 (d, 1H), 5.23-5.12 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95(m, 1H), 3.81-3.71 (m, 1H), 3.46 (s, 3H), 3.34-3.26 (m, 1H), 3.19-3.00(m, 3H), 2.99-2.82 (m, 2H), 1.92-1.77 (m, 2H) (one exchangeable protonnot observed).

LCMS (10 cm_ESCI_Formic_MeCN) t_(R) 2.48 (min) m/z 375 (MH⁺).

Example 2 (Alternative Synthesis)(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamidei) 5-Chloro-1,3-benzoxazol-2(3H)-one

To a solution of 2-amino-4-chlorophenol (400 g, 2.79 mol) in 2-MeTHF (6L) was added CDI (497 g, 3.07 mol) under N₂ (exotherm 11.0° C.-22.0°C.). The reaction mixture was heated at reflux for 1 h. The mixture wascooled to rt, washed with 2 M HCl(aq) (6 L), 8% NaHCO₃(aq) (6 L) andbrine (3 L). The organic layer was dried over MgSO₄, filtered andevaporated. This gave the product as a pale brown solid (456.1 g, 97%yield, LC purity >99%).

¹H NMR (270 MHz, DMSO-d₆): δ 12.0-11.5 (br s, 1H), 7.31 (d, 1H), 7.12(m, 2H).

LCMS (5 cm_ESCI, aq. formic acid_methanol) t_(R) 3.87 (min) m/z 169.8(MUFF).

ii) 5-Chloro-3-methyl-1,3-benzoxazol-2(3H)-one

To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (stage i) (1111.8 g,6.56 mol) in DMF (4.12 L) was added Cs₂CO₃ (2136.4 g, 6.56 mol)maintaining the temperature between 0-5° C. MeI (450 ml, 7.21 mol) wasthen added slowly maintaining the temperature between 0-5° C. Thereaction mixture was allowed to warm-up to rt and stirred overnight. Themixture was cooled to 0-5° C. and H₂O (4.12 L) was added slowly. Thereaction mixture was then warmed to rt and stirred for 15 min. Thesolids were filtered off and washed with water (4×980 ml). The filtercake was dried under vacuum at 55° C. overnight (1149.9 g, 96% yield, LCpurity >99%, H₂O: (Karl Fischer) 0.1%).

¹H NMR (270 MHz, DMSO-d₆): δ 7.45 (d, 1H), 7.35 (d, 1H), 7.15 (dd, 1H),3.35 (s, 3H).

LCMS (5 cm_ESCI_aq. formic acid_methanol) t_(R) 4.13 (min) m/z 183.8(M⁺).

iii)3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one

A solution of 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (stage ii))(350 g, 1.91 mol), B₂pin₂ (581.0 g, 2.29 mol) and KOAc (561.3 g, 5.72mol) was vacuum degassed and purged with N₂ (×3). Pd(OAc)₂ (12.9 g, 57.2mmol) and XPhos (54.6 g, 114 mmol) were added and the mixture was vacuumdegassed and purged with N₂ (×3). The mixture was heated to 75° C. Alarge exotherm was observed at −70° C. which warmed-up the mixture toreflux (100° C.). The reaction mixture was stirred for 1 h with noheating. HPLC analysis indicated 2.5% of the starting material remainingtherefore the mixture was heated at 85° C. for 1 h. At this stage, nofurther change was observed. Additional portions of B₂pin₂ (14.6 g, 57.2mmol), KOAc (5.7 g, 57.2 mmol), Pd(OAc)₂ (12.9 g, 57.2 mmol) and XPhos(27.3 g, 57.2 mmol) were added and the mixture was stirred for 1 h at75° C. HPLC analysis showed no starting material remaining. The mixturewas cooled to rt, filtered through a pad of Celite (501 g) and the cakewas washed with EtOAc (2240 ml). The filtrate was combined with twoother batches prepared in the same way (2×350 g) and evaporated. Thisgave 1865.1 g of the product as a grey solid (97% yield, 90.0% pure byLC, 82±2% pure by ¹H NMR (DMSO-d₆) assay vs TCNB).

¹H NMR (270 MHz, DMSO-d₆): δ 7.40-7.50 (m, 2H), 7.30 (d, 1H), 3.40 (s,3H), 1.30 (s, 12H).

LCMS (5 cm_ESCI_aq. formic acid_methanol_) t_(R) 4.91 (min) m/z 276.1(MH⁺).

iv)Nα-(tert-Butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide

To a suspension of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(stage iii)) (859 g, 700 g active, 2.544 mol) and tert-butyl(S)-1-carbamoyl-2-(4-iodophenyl)ethylcarbamate (prepared according tothe procedure in WO 2009/074829 p. 47), (903 g, 2.313 mol) in dioxane(4.1 L) was added 2 M K₂CO₃ (2.3 L). The suspension was vacuum degassedand purged with N₂ (×3). Pd(dppf)Cl₂.DCM (28.33 g, 0.0347 mol) was addedand the reaction mixture was heated at 75° C. for 3 h. The mixture wascooled to rt and diluted with water (6.4 L). The suspension was stirredat rt overnight; the solid was filtered off and washed with water (3×1L). The product was dried at 45° C. for 3 days (1269.1 g, yield 133%—by¹H NMR contains pinacol related impurity and dioxane, LC 94.3% pure,H₂O: (Karl Fischer) 3.35%).

¹H NMR (270 MHz, DMSO-d₆): δ 7.62-7.34 (m, 7H), 7.04 (brs, 2H), 6.86 (d,1H) 4.12 (m, 1H), 3.40 (s, 3H), 3.00 (dd, 1H), 2.78 (dd, 1H), 1.30 (s,9H).

LCMS (5 cm ESI Water MeCN) t_(R) 4.51 (min) m/z 312 (MH⁺).

v)4-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide

To a very thick suspension ofNa-(tert-butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide(stage iv)) (1269 g, active 952 g assumed 100% conversion at stage iv),2.3138 mol) in DCM (2.1 L) under N₂ was added dropwise 4.1 M HCl indioxane (2.7 L, 11.06 mol) over 1 h maintaining the temperature at ˜15°C. (suspension became more mobile after addition of approx. 0.5 L of 4.1M HCl dioxane). After 2 h, the mixture was diluted with water (5.6 L)and stirred for 30 min at rt. The mixture was then filtered through apad of Celite (500 g) to remove undissolved material—very slowfiltration; the Celite was checked for product by LC. The pad was washedwith water (400 ml). The layers DCM/dioxane-water were separated. Theaqueous layer was cooled to ˜5° C. and 35% NH₃ (aq) (700 ml) was addedslowly to achieve pH=9-10. The suspension was stirred overnight then theproduct was filtered off and washed with water (3×400 ml). The productwas dried at 45° C. in vacuo for 2 days (off white solid, 489.4 g, 68%yield over two stages, 99.4% pure by LC, >99% EP, 98±2% pure by ¹H NMRassay vs TCNB in DMSO, H₂O: (Karl Fischer) 0.92%).

¹H NMR (270 MHz, DMSO-d₆): δ 7.59-7.30 (m, 7H), 6.98 (brs, 1H), 3.36 (m,4H), 2.95 (dd, 1H), 2.67 (dd, 1H) 1.86 (brs, 2H).

LCMS (5 cm ESI Water MeCN) t_(R) 2.76 (min) m/z 312 (MH⁺).

vi) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

To a solution of4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide(stage v)) (756 g, active 733 g, 2.354 mol) and(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (577 g,2.354) (Intermediate 3) in DMF (3 L) was added DiPEA (1230 ml, 7.062mol) under N₂. T3P in DMF (50% w/w, 1924 ml, 3.296 mol) was addeddropwise over 1.5 h maintaining the temperature <25° C. After 30 min, LCcompletion check indicated completion of the coupling reaction. DiPEA(1230 ml, 7.062 mol) was then added and the reaction mixture was heatedto 50° C. T3P in DMF (50% w/w, 3986 ml, 6.827 mol) was added portionwiseover 1 h (no exotherm observed). The reaction mixture was stirred at 50°C. for 4 h and then at rt overnight. The mixture was cooled to 10° C.,diluted with 2-MeTHF (4 L) and water (5.6 L, exothermic). The layerswere separated and the aqueous layer was extracted with 2-MeTHF (2×4 L).The combined organic extracts were dried over MgSO₄, filtered andconcentrated under reduced pressure. This delivered the product as apale brown solid in 98% yield (1242 g (active 1205 g), corrected yield98%, LC purity 98.4%, ¹H NMR assay vs TCNB 97±2%, main impurities by ¹HNMR: 2-MeTHF 1.9%, DMF 0.6%).

vii)(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

A solution of tert-butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate(stage vi)) (1776 g, active 1671 g, 3.210 mol) in formic acid/water (4.2L/440 ml) was stirred on a buchi at 35-37° C. under reduced pressure(300-500 mbar). After 3 h, LCMS completion check indicated 93.95% of theproduct and 0.5% of the starting material. The mixture was concentrated(4 h) to give an oily residue. The residue was dissolved in water (4.4L) and washed with TBME (2.2 L). The aqueous layer was vigorouslystirred and treated with NH₃(aq) (1.8 L) at <25° C. to achieve pH=9-10.The mixture was stirred at rt for 3 h. The solid was filtered off andwashed with water (3×1 L). The filter cake was dried at 45° C.overnight. This gave the product as a pale brown solid (1498 g, active1333 g, LC 91.5%, ¹H NMR assay vs TCNB 89±2%, H₂O: (Karl Fischer)4.63%).

The crude product was re-crystallised from EtOH/H₂O in two batches(2×747 g).

Batch A: The crude product (747 g) was dissolved in EtOH (8 L) at refluxunder N₂. Water (1.6 L) was added slowly. The mixture was hot filtered(65° C.) to remove black particles (filtrate temperature 50° C.) andthen stirred at 40° C. overnight. The suspension was cooled to 10° C.over 4 h and held at that temperature for 3 h. The product was filteredoff and washed with EtOH/H₂O (8:2, 3×500 ml) then water (3×500 ml). Thefilter cake was dried at 45° C. overnight (473 g, 97.7% pure by LC, Pdlevel 71.4 ppm).

Batch B gave 436 g of the product (95.8% pure by LC, Pd level 65.8 ppm).

The liquors from both batches were combined and concentrated to ˜8 L.The liquors were left overnight at rt. The solids were filtered off andwashed with EtOH/H₂O (8:2, 3×400 ml) then water (3×400 ml). The productwas dried at 45° C. overnight. This gave additional 88 g of the product(LC purity 95.0%).

The products (LC purity of the blend 95.69%) were re-crystallised fromEtOH/H₂O in two batches (Batch C: 520 g, Batch D: 520 g).

Batch C: The crude product (520 g) was dissolved in EtOH (6.24 L) atreflux under N₂. Water (1248 ml) was added slowly. The mixture wasallowed to cool down to 40° C. (3 h), seeded with 0.5 g of the titlecompound and stirred at 40° C. for 10 h. The mixture was then cooled to26° C. over 7 h. The resulting suspension was cooled to 10° C. andstirred at that temperature for 6 h. The product was filtered off,washed with EtOH/water (8:2, 3×500 ml) and water (3×500 ml). The filtercake was dried at 45° C. for 2 d. The product was obtained as a greysolid (418 g, yield ˜56%, LCMS purity 97.5%, chiral LC 100%, ¹H NMR(DMSO-d₆) assay vs TCNB 100±2%).

Batch D: 418 g, yield ˜56%, LCMS purity 97.5%, chiral LC 100%, ¹H NMR(DMSO-d₆) assay vs TCNB 100±2%

The product was blended with the material from an intermediate scalereaction performed in the same way and re-analysed (968 g, LC purity98.04%, chiral LC 100%, ¹H NMR assay vs TCNB 99±2%, 0.35% EtOH by ¹HNMR, H₂O: (Karl Fischer) 4.58%, Pd 57.6 ppm, XRPD (X-ray powderdiffraction) Form A.

TABLE 1 Five peaks of highest intensity of Example 2, Form A °2-thetaRelative intensity 12.2 str 14.3 str 16.2 str 19.1 med 20.6 vs

TABLE 2 Ten peaks of highest intensity of Example 2, Form A °2-thetaRelative intensity 8.9 w 12.2 str 14.3 str 16.2 med 17.9 vw 19.1 med20.6 vs 25.0 w 28.9 w 34.7 w

Example 2, Preparation of Crystalline Form B

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,Form A (5 g), prepared by the process described above, was charged intoa reaction vessel. Acetone (35 ml) was added and the mixture heated to60-65° C. in a heating block. The resulting solution was left to cool tort by switching the heating block off. The resulting suspension wasfiltered and the filtrate dried in a vacuum oven at 40° C. and <600 mbarovernight. XRPD (X-ray powder diffraction), Form B.

TABLE 3 Five peaks of highest intensity of Example 2, Form B °2-thetaRelative intensity 12.3 str 14.3 str 15.6 vs 16.3 str 17.2 str

TABLE 4 Ten peaks of highest intensity of Example 2, Form B °2-thetaRelative intensity 12.3 str 14.3 str 15.6 vs 16.3 str 17.2 str 18.3 med18.5 med 19.7 med 21.2 w 23.6 w

Example 2, Preparation of Crystalline Form C

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,Form A (50 mg), prepared by the process described above, was chargedinto a 1.5 mL scintillation vial. Propan-2-ol (1 ml) was added and themixture placed in a orbital shaker fitted with a heating block at 500rpm and approximately 40° C. for 1 day. The resulting suspension wasfiltered and the filtrate dried. XRPD (X-ray powder diffraction), FormC.

TABLE 5 Five peaks of highest intensity of Example 2, Form C °2-thetaRelative intensity 9.0 vs 14.0 med 16.0 str 16.4 str 21.0 str

TABLE 6 Ten peaks of highest intensity of Example 2, Form C °2-thetaRelative intensity 7.8 w 9.0 vs 14.0 med 14.4 med 16.0 str 16.4 vs 17.9w 18.9 med 19.6 w 21.0 med

Example 2, Preparation of Xinafoate Salt, Crystalline Form A

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,Form A (100 mg), prepared by the process described above, was chargedinto a 1.5 mL scintillation vial. Approximately 48 mg of1-hydroxy-2-naphthoic acid was added. Subsequently 1.5 mL of ACN and0.03 mL of water were added and the mixture was stirred at rt forapproximately 6 h using a magnetic stirring bar. The vial was closedduring the stirring. The resulting suspension was centrifuged at 7500rpm for 5 min and the supernatant removed with a pasteur pipette. Thewet solid residue was dried in a vacuum oven at 30° C. and 30 mbar forapproximately 60 h. XRPD (X-ray powder diffraction), xinafoate salt ofForm A.

TABLE 7 Five peaks of highest intensity of Example 2, xinafoate salt ofcrystalline Form A °2-theta Relative intensity 7.4 vs 12.5 med 13.0 str15.1 vs 15.5 str

TABLE 8 Ten peaks of highest intensity of Example 2, xinafoate salt ofcrystalline Form A °2-theta Relative intensity 7.4 vs 10.2 med 12.5 med13.0 str 13.6 med 14.8 med 15.1 vs 15.5 str 15.7 med 17.9 med

Example 2, Preparation of R-Mandalate Salt, Crystalline Form A

(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,Form A (120 mg), prepared by the process described above, was chargedinto a 1.5 mL scintillation vial. Approximately 45 mg of R-(−)-mandelicacid was added. Subsequently 1.5 mL of ACN and 0.04 mL of water wereadded and the mixture was stirred at rt for approximately 6 h using amagnetic stirring bar. The vial was closed during the stirring. Theresulting suspension was centrifuged at 7500 rpm for 5 min and thesupernatant removed with a pasteur pipette. The wet solid residue wasdried in a vacuum oven at 30° C. and 30 mbar for approximately 60 h.XRPD (X-ray powder diffraction), R-mandelate salt of Form A.

TABLE 9 Five peaks of highest intensity of Example 2, R-mandelate saltof crystalline Form A °2-theta Relative intensity 13.0 med 14.5 med 15.5vs 17.0 med 21.4 med

TABLE 10 Ten peaks of highest intensity of Example 2, R-mandelate saltof crystalline Form A °2-theta Relative intensity 8.0 w 13.0 med 14.5med 15.5 vs 15.7 w 15.9 med 17.0 med 18.2 w 18.7 w 21.4 med

Example 3 (Method A)(2S)—N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

i) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3,7-dimethyl-1,3-benzoxazol-2(3H)-one(Boronate ester 1, 154 mg, 0.56 mmol) and tert-butyl(2S)-2-{[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate(Intermediate 5, 266 mg, 0.53 mmol) were dissolved in ACN (13 mL) andwater (0.5 mL). Potassium carbonate (110 mg, 0.80 mmol) was added andthe reaction mixture was degassed for 20 min before the addition ofPd(dppf)Cl₂.DCM (43 mg, 0.053 mmol). The reaction mixture was heated at80° C. for 90 min. After this time the reaction was concentrated underreduced pressure and purified by silica gel column chromatographyeluting with a gradient of 0-80% EtOAc in iso-hexane to afford thesubtitled compound as a light brown solid (242 mg, 85%). ¹H NMR (400MHz, CDCl₃): δ 7.55 (d, 2H), 7.36 (d, 2H), 7.16-7.02 (m, 3H), 6.96 (s,1H), 5.16 (s, 1H), 4.17-4.00 (m, 3H), 3.56-3.48 (m, 1H), 3.53-3.36 (m,3H), 3.21-3.12 (m, 2H), 2.44 (s, 3H), 1.95 (d, 2H), 1.47 (s, 9H),0.94-0.87 (m, 2H).

ii)(2S)—N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate(240 mg, 0.45 mmol) was dissolved in formic acid (3 mL) and heated at50° C. for 10 min on a pre-heated stirrer hotplate. After this time thereaction was concentrated under reduced pressure, dissolved in DCM andwashed with saturated sodium hydrogen carbonate solution. The organicextract was dried (phase separator cartridge) and concentrated underreduced pressure. The solid was purified by silica gel columnchromatography eluting with 0-2% methanolic ammonia (7 N) in DCM toafford the title compound as a white solid (54 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (d, 1H), 7.65 (d, 2H), 7.38 (d, 3H),7.28 (s, 1H), 5.03 (q, 1H), 4.00 (dd, 1H), 3.90-3.82 (m, 1H), 3.73 (ddd,1H), 3.39 (s, 3H), 3.32 (s, 3H), 3.24-3.13 (m, 2H), 3.04 (dd, 1H),2.82-2.74 (m, 1H), 2.38 (s, 2H), 1.80-1.68 (m, 2H) (one exchangeableproton not observed).

LCMS (10 cm_ESCI_Formic_MeCN) t_(R) 2.58 (min) m/z 435 (MH⁺).

Example 4 (Method B)4′-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-ylmethanesulfonate

i) tert-Butyl(2S)-2-{[(2S)-1-amino-3-{3′-[(methylsulfonyl)oxy]biphenyl-4-yl}-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate

A suspension of tert-butyl(2S)-2-[[(1S)-2-amino-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]carbamoyl]-1,4-oxazepane-4-carboxylatetert-butyl2-({(2S)-1-amino-1-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl}carbamoyl)-1,4-oxazepane-4-carboxylate(Intermediate 6, 0.21 g, 0.4 mmol), (3-iodophenyl) methanesulfonate(0.13 g, 0.44 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in ACN(30 mL) and water (1.2 mL) were degassed under nitrogen for 10 min.Pd(dppf)Cl₂.DCM complex (0.032 g, 10 mol %) was added and the reactionmixture was heated at 80° C. for 120 min. The solvent was removed underreduced pressure and the residue was treated with water (20 mL) and DCM(25 mL). The DCM was dried (phase separating cartridge) and evaporatedunder reduced pressure to give the subtitled compound as a dark brownglass (0.24 g, >100%). ¹H NMR (400 MHz, CDCl₃): δ 7.54-7.43 (m, 5H),7.35-7.19 (m, 3H), 5.58 (m, 1H), 4.71 (s, 1H), 4.21-3.94 (m, 3H),3.81-3.76 (m, 1H), 3.52-3.44 (m, 3H), 3.23-3.14 (m, 4H), 2.80 (s, 1H),2.20-1.54 (m, 1H), 1.45 (s, 9H) (three exchangeable protons notobserved).

ii) tert-Butyl(2S)-2-{[(1S)-cyano-2-{3′-[(methylsulfonyl)oxy]biphenyl-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

Burgess reagent (0.11 g, 0.046 mmol) was added to a stirred solution oftert-butyl(2S)-2-{[(2S)-1-amino-3-{3′-[(methylsulfonyl)oxy]biphenyl-4-yl}-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate(0.24 g) in DCM (20 mL). After 3 days additional reagent (0.11 g, 0.046mmol) was added and stirring was continued for 6 h. The reaction wasallowed to stand overnight before washing with water (20 mL). Theorganic extract was dried (phase separating cartridge) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography eluting with 0-100% EtOAc in iso-hexane to give thesubtitled compound as a colourless glass (0.18 g, 83% over two steps).¹H NMR (400 MHz, CDCl₃): δ 7.61-7.45 (m, 5H), 7.38 (m, 3H), 7.06 (s,1H), 5.17 (s, 1H), 4.20-3.99 (m, 2H), 3.75-3.63 (m, 1H), 3.57-3.37 (m,3H), 3.49-2.85 (m, 3H), 1.94 (s, 2H), 1.57 (s, 1H), 1.51-1.35 (m, 9H),1.33 (s, 1H) (one exchangeable proton not observed).

iii)4′-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-ylmethanesulfonate

A solution of tert-butyl(2S)-2-{[(1S)-1-cyano-2-{3′-[(methylsulfonyl)oxy]biphenyl-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate(0.18 g, 0.33 mmol) in formic acid (3 mL) was heated at 50° C. for 15min. The mixture was evaporated under reduced pressure. The residue wasdissolved in DCM (20 mL) and stirred with saturated sodium bicarbonate(30 mL). The layers were separated and the organic extract was dried(phase separating cartridge) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting with 2%7 N methanolic ammonia in DCM. The resultant solid which wasrecrystallized from 1:1 di-isopropyl ether:EtOAc to afford the titlecompound as a colourless solid (50 mg, 34%). ¹H NMR (400 MHz, CDCl₃): δ7.61-7.46 (m, 5H), 7.40 (dd, 2H), 7.38-7.18 (m, 1H), 7.18 (d, 1H),5.23-5.12 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.71 (m,1H), 3.35-3.26 (m, 1H), 3.22-3.09 (m, 4H), 3.07-2.81 (m, 3H), 1.91-1.77(m, 2H) (two exchangeable protons not observed).

LCMS (10 cm_ESCI_Bicarb_MeCN) t_(R) 2.75 (min) m/z 444 (MH⁺).

Examples 5-33

The following compounds were prepared in using the aforementionedmethods and intermediates:

Example 5(2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester:Commercial Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.79-7.75 (m, 2H), 7.63-7.58 (m, 3H), 7.43(d, 2H), 7.20 (d, 1H), 5.21 (dt, 1H), 4.10 (dd, 1H), 3.99 (dt, 1H), 3.76(ddd, 1H), 3.32 (dd, 1H), 3.20- 3.12 (m, 2H), 3.05 (dd, 1H), 2.96 (dt,1H), 2.91-2.82 (m, 1H), 2.63 (s, 3H), 1.91-1.77 (m, 2H) (oneexchangeable proton not observed). m/z: 405 Example 6(2S)-N-{(1S)-1-Cyano-2-[4′-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: CommercialIntermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.74-7.64 (m, 4H), 7.62-7.55 (m, 2H), 7.43(d, 2H), 7.20 (d, 1H), 5.21 (dt, 1H), 4.09 (dd, 1H), 3.98 (dt, 1H), 3.75(ddd, 1H), 3.30 (dd, 1H), 3.16 (d, 2H), 3.07-2.80 (m, 3H), 1.92-1.76 (m,2H) (one exchangeable proton not observed). m/z: 418 Example 7(2S)-N-[(1S)-1-Cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: CommercialIntermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.54-7.49 (m, 2H), 7.41-7.34 (m, 3H),7.48-7.05 (m, 3H), 5.23-5.16 (m, 1H), 4.09 (dd, 1H), 4.03-3.95 (m, 1H),3.75 (ddd, 1H), 3.30 (dd, 1H), 3.18- 3.10 (m, 2H), 3.04 (dd, 1H),3.00-2.90 (m, 1H), 2.92-2.82 (m, 1H), 1.88-1.78 (m, 2H) (oneexchangeable proton not observed). m/z: 386 Example 8(2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: CommercialIntermediate: 5

¹H NMR (400 MHz, DMSO-d₆): δ 9.10 (dd, 1H), 8.64 (d, 1H), 8.38-8.33 (m,1H), 8.15- 8.08 (m, 1H), 7.81 (t, 2H), 7.48 (d, 2H), 5.10-5.01 (m, 1H),4.00 (dd, 1H), 3.85 (ddd, 1H), 3.76-3.67 (m, 1H), 3.33-3.18 (m, 3H),3.02 (dd, 1H), 2.81-2.70 (m, 1H), 2.64-2.55 (m, 1H), 1.78-1.65 (m, 2H)(one exchangeable proton not observed). m/z: 376 Example 9(2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 20 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.60-7.53 (m, 2H), 7.46-7.37 (m, 3H),7.28-7.23 (m, 2H), 7.22 (d, 1H), 5.23-5.16 (m, 1H), 4.10 (dd, 1H),4.03-3.95 (m, 1H), 3.75 (ddd, 1H), 3.51 (s, 3H), 3.45 (s, 2H), 3.31 (dd,1H), 3.19-3.11 (m, 2H), 3.04 (dd, 1H), 3.01-2.91 (m, 1H), 2.92-2.82 (m,1H), 1.89-1.78 (m, 2H) (one exchangeable proton not observed). m/z: 451Example 10(2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 4 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.53 (t, 2H), 7.40 (d, 2H), 7.19 (d, 1H),7.12 (s, 1H), 6.99-6.96 (m, 1H), 5.19 (dt, 1H), 4.10 (dd, 1H), 4.04-3.90(m, 3H), 3.75 (ddd, 1H), 3.32 (dd, 1H), 3.16-3.10 (m, 2H), 3.04 (dd,1H), 2.96 (dt, 1H), 2.92-2.84 (m, 1H), 2.44 (s, 3H), 1.89-1.78 (m, 2H),1.41 (t, 3H) (one exchangeable proton not observed). m/z: 449 Example 11(2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared usingMethod A Boronate ester: 5 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.53-7.46 (m, 2H), 7.39-7.34 (m, 3H),7.20-7.11 (m, 3H), 5.21-5.14 (m, 1H), 4.12-4.07 (m, 1H), 4.02-3.94 (m,3H), 3.75 (ddd, 1H), 3.31 (dd, 1H), 3.15-3.10 (m, 2H), 3.03 (dd, 1H),2.99-2.91 (m, 1H), 2.91-2.82 (m, 1H), 1.90-1.78 (m, 2H), 1.63 (s, 6H)(two exchangeable protons not observed). m/z: 479 Example 12(2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared usingMethod A Boronate ester: 7 Intermediate: 5

¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (d, 1H), 7.69 (d, 2H), 7.60 (s, 1H),7.48 (dd, 1H), 7.42 (d, 2H), 6.59-6.29 (m, 1H), 5.04 (q, 1H), 4.42 (td,2H), 4.00 (dd, 1H), 3.85 (ddd, 1H), 3.72 (ddd, 1H), 3.27-3.15 (m, 2H),3.03 (dd, 1H), 2.81-2.73 (m, 1H), 2.64-2.51 (m, 2H), 1.78-1.68 (m, 2H)(one exchangeable proton not observed). m/z: 489 Example 13(2S)-N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide Prepared usingMethod A Boronate ester: 8 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.57-7.50 (m, 2H), 7.44-7.36 (m, 2H),7.33-7.22 (m, 2H), 7.22-7.15 (m, 2H), 5.20 (dt, 1H), 4.12-4.07 (m, 1H),4.03-3.94 (m, 3H), 3.75 (ddd, 1H), 3.35-3.28 (m, 1H), 3.17-3.12 (m, 2H),3.05 (dd, 1H), 3.00-2.92 (m, 1H), 2.92-2.84 (m, 1H), 2.71 (t, 2H), 2.33(s, 6H), 1.89-1.78 (m, 2H) (one exchangeable proton not observed). m/z:478 Example 14(2S)-N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 9 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.60 (dd, 3H), 7.44 (d, 2H), 7.36 (d, 1H),7.20 (d, 1H), 7.06 (s, 1H), 5.21 (dd, 1H), 4.11 (dd, 1H), 4.00 (dt, 1H),3.79-3.74 (m, 1H), 3.36-3.26 (m, 4H), 3.16 (d, 2H), 3.05 (dd, 1H),2.97-2.86 (m, 2H), 1.86-1.80 (m, 2H) (one exchangeable proton notobserved). m/z: 455 Example 15(2S)-N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 6 Intermediate: 5

¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (d, 1H), 7.71 (d, 2H), 7.49 (s, 1H),7.42 (t, 3H), 5.04 (q, 1H), 4.00 (d, 1H), 3.89-3.82 (m, 1H), 3.73 (d,1H), 3.39-3.10 (m, 4H), 3.03 (d, 1H), 2.81-2.73 (m, 1H), 2.65-2.53 (m,2H), 2.22 (s, 1H), 1.73 (s, 2H) (one exchangeable proton not observed).m/z: 439 Example 16(2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 3 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.58-7.51 (m, 2H), 7.41 (d, 2H), 7.33-7.26(m, 2H), 7.20 (d, 1H), 7.15 (d, 1H), 5.20 (dt, 1H), 4.10 (dd, 1H),4.04-3.90 (m, 3H), 3.75 (ddd, 1H), 3.31 (dd, 1H), 3.20-3.10 (m, 2H),3.04 (dd, 1H), 2.96 (dt, 1H), 2.91-2.82 (m, 1H), 1.92-1.77 (m, 2H), 1.42(t, 3H) (one exchangeable proton not observed). m/z: 435 Example 17(2S)-N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 10 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.57-7.50 (m, 2H), 7.42-7.33 (m, 2H),7.35-7.25 (m, 4H), 5.20 (dt, 1H), 4.10 (dd, 1H), 3.99 (dt, 1H),3.79-3.70 (m, 3H), 3.31 (dd, 1H), 3.20-3.12 (m, 2H), 3.05 (dd, 1H), 2.96(dt, 1H), 2.91-2.82 (m, 1H), 1.91-1.77 (m, 2H), 1.33-1.23 (m, 1H),0.66-0.59 (m, 2H), 0.50-0.44 (m, 2H) (one exchangeable proton notobserved). m/z: 461 Example 18(2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 11 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, 2H), 7.48 (d, 1H), 7.43-7.32 (m,4H), 7.21 (d, 1H), 5.21 (dt, 1H), 4.19 (t, 2H), 4.10 (dd, 1H), 3.99 (dt,1H), 3.80-3.70 (m, 3H), 3.43-3.21 (m, 4H), 3.23-3.09 (m, 2H), 3.05 (dd,1H), 3.00-2.82 (m, 2H), 1.93-1.77 (m, 2H) (one exchangeable proton notobserved). m/z: 481 Example 19(2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 12 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.61-7.51 (m, 2H), 7.40 (dd, 2H), 7.30-7.24(m, 3H), 7.21 (d, 1H), 5.24-5.14 (m, 1H), 4.65-4.55 (m, 1H), 4.13-4.07(m, 1H), 4.05-3.95 (m, 1H), 3.82-3.72 (m, 1H), 3.36-3.27 (m, 1H),3.19-3.11 (m, 2H), 3.05 (dd, 1H), 2.99-2.82 (m, 2H), 1.93-1.76 (m, 2H),1.59 (d, 6H) (one exchangeable proton not observed). m/z: 449 Example 20(2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 13 Intermediate: 5

¹H NMR (400 MHz, DMSO-d₆): δ 7.54 (d, 2H), 7.43-7.33 (m, 2H), 7.24-7.18(m, 2H), 7.15 (d, 1H), 7.06 (d, 1H), 5.23-5.13 (m, 1H), 4.66 (s, 2H),4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.71 (m, 1H), 3.43 (s, 3H),3.37-3.28 (m, 1H), 3.17-3.10 (m, 2H), 3.09-2.99 (m, 1H), 2.99-2.82 (m,2H), 1.93-1.77 (m, 2H) (one exchangeable proton not observed) m/z: 435Example 21(2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 21 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.60-7.51 (m, 2H), 7.39 (dd, 2H), 7.34-7.24(m, 3H), 7.20 (d, 1H), 5.23-5.14 (m, 1H), 4.12-3.95 (m, 4H), 3.81-3.70(m, 3H), 3.43-3.20 (m, 4H), 3.19-3.10 (m, 2H), 3.04 (dd, 1H), 2.99-2.82(m, 2H), 1.92-1.77 (m, 2H) (one exchangeable proton not observed). m/z:465 Example 22(2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: CommercialIntermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.61-7.56 (m, 3H), 7.40 (d, 2H), 7.31-7.25(m, 1H), 7.20 (d, 1H), 5.19 (dt, 1H), 4.09 (dd, 1H), 3.99 (dt, 1H), 3.75(ddd, 1H), 3.30 (dd, 1H), 3.13 (d, 2H), 3.07-2.81 (m, 3H), 1.91-1.76 (m,2H) (one exchangeable proton not observed). m/z: 381 Example 23(2S)-N-[(1S)-2-(4′-Carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: CommercialIntermediate: 5

¹H NMR (400 MHz, DMSO-d₆): δ 8.65-8.58 (m, 1H), 7.78-7.69 (m, 4H),7.67-7.55 (m, 3H), 7.41 (d, 2H), 5.09-4.99 (m, 1H), 3.99 (dd, 1H), 3.84(ddd, 1H), 3.76-3.67 (m, 1H), 3.29-3.15 (m, 2H), 3.02 (dd, 1H),2.80-2.68 (m, 1H), 2.63-2.49 (m, 2H), 1.79-1.64 (m, 2H) (oneexchangeable proton not observed). m/z: 411 Example 24(2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: 14Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, 1H), 7.68-7.60 (m, 3H), 7.52 (s,1H), 7.45 (dd, 3H), 7.21 (d, 1H), 6.73 (d, 1H), 5.25-5.18 (m, 1H), 4.10(dd, 1H), 4.04-3.96 (m, 1H), 3.83- 3.69 (m, 4H), 3.32 (dd, 1H),3.19-3.15 (m, 2H), 3.05 (dd, 1H), 3.00-2.92 (m, 1H), 2.91- 2.83 (m, 1H)1.89-1.78 (m, 2H), (one exchangeable proton not observed). m/z: 431Example 25(2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Preparedusing Method A Boronate ester: 15 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.53 (t, 2H), 7.42 (d, 2H), 7.33-7.26 (m,2H), 7.21 (d, 1H), 7.12 (d, 1H), 5.23-5.16 (m, 1H), 4.10 (dd, 1H),4.03-3.96 (m, 3H), 3.80-3.72 (m, 3H), 3.40-3.27 (m, 3H), 3.17-3.13 (m,2H), 3.07-2.83 (m, 3H), 2.19 (ddd, 1H), 1.90-1.79 (m, 2H), 1.54-1.42 (m,3H), (one proton under water peak and one exchangeable proton notobserved). m/z: 505 Example 26(2S)-N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 16 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.56-7.52 (m, 2H), 7.42 (d, 2H), 7.31 (d,1H), 7.19 (d, 1H), 7.03 (d, 1H), 5.20 (dt, 1H), 4.10 (dd, 1H), 4.00 (dt,1H), 3.76 (ddd, 1H), 3.46 (s, 3H), 3.31 (dd, 1H), 3.16-3.12 (m, 2H),3.04 (dd, 1H), 3.00-2.84 (m, 2H), 1.89-1.80 (m, 2H), 1.25 (s, 1H). m/z:455 Example 27(2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 17 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, 2H), 7.41 (d, 2H), 7.36 (dd, 1H),7.30 (d, 1H), 7.24 (s, 1H), 7.19 (d, 1H), 6.28-5.95 (m, 1H), 5.23-5.16(m, 1H), 4.28-4.17 (m, 2H), 4.10 (dd, 1H), 4.03-3.95 (m, 1H), 3.75 (ddd,1H), 3.31 (dd, 1H), 3.20-3.12 (m, 2H), 3.04 (dd, 1H), 3.00-2.82 (m, 2H),1.91-1.77 (m, 2H) (one exchangeable proton not observed). m/z: 471Example 28(2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide Prepared usingMethod A Boronate ester: 18 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.56-7.49 (m, 2H), 7.45-7.29 (m, 4H),7.24-7.15 (m, 2H), 5.23-5.16 (m, 1H), 4.47 (q, 2H), 4.10 (dd, 1H),4.03-3.95 (m, 1H), 3.75 (ddd, 1H), 3.31 (dd, 1H), 3.20-3.12 (m, 2H),3.04 (dd, 1H), 3.00-2.82 (m, 2H), 1.90-1.77 (m, 2H) (one exchangeableproton not observed). m/z: 489 Example 29(2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method ABoronate ester: 19 Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, 2H), 7.53-7.48 (m, 1H), 7.44-7.35(m, 3H), 7.22- 7.17 (m, 2H), 5.21 (dt, 1H), 4.10 (dd, 1H), 3.99 (dt,1H), 3.76 (ddd, 1H), 3.52 (s, 3H), 3.31 (dd, 1H), 3.17-3.12 (m, 2H),3.05 (dd, 1H), 2.99-2.92 (m, 1H), 2.91-2.84 (m, 1H), 1.89- 1.80 (m, 2H)(one exchangeable proton not observed). m/z: 437 Example 30(2S)-N-{(1S)-1-Cyano-2-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide Prepared using Method B Aryl iodide: CommercialIntermediate: 6

¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, 2H), 7.77 (d, 2H), 7.61 (d, 2H),7.44 (dd, 2H), 7.29-7.16 (m, 1H), 5.25-5.13 (m, 1H), 4.12-4.06 (m, 1H),4.05-3.95 (m, 1H), 3.77 (dtd, 1H), 3.36-3.28 (m, 1H), 3.17 (t, 2H),3.14-2.97 (m, 2H), 3.00-2.82 (m, 6H), 1.91-1.77 (m, 1H). m/z: 428Example 31(2S)-N-{(1S)-2-[4′-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide Prepared using Method B Aryl iodide: CommercialIntermediate: 6

¹H NMR (400 MHz, CDCl₃): δ 7.92 (d, 2H), 7.77 (d, 2H), 7.66-7.56 (m,2H), 7.44 (dd, 2H), 7.31-7.14 (m, 1H), 5.25-5.12 (m, 1H), 4.13-4.07 (m,1H), 4.06-3.95 (m, 1H), 3.86- 3.69 (m, 5H), 3.36-3.27 (m, 1H), 3.24-3.10(m, 2H), 3.10-2.84 (m, 3H), 2.12 (m, 2H), 1.91-1.76 (m, 2H) (oneexchangeable proton not observed). m/z: 469 Example 32(2S)-N-[(1S)-1-Cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamidePrepared using Method A Boronate ester: Commercial Intermediate: 5

¹H NMR (400 MHz, CDCl₃): δ 7.56-7.51 (m, 4H), 7.38 (d, 2H), 7.21-7.08(m, 3H), 5.20 (dt, 1H), 4.09 (dd, 1H), 3.98 (dt, 1H), 3.74 (ddd, 1H),3.30 (dd, 1H), 3.13 (d, 2H), 3.03 (dd, 1H), 2.98-2.81 (m, 2H), 1.89-1.76(m, 2H) (one exchangeable proton not observed). m/z: 368 Example 33(2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide Prepared using Method A Boronate ester: CommercialIntermediate: 5

¹H NMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 8.61 (d, 1H), 8.33 (d, 1H),8.23 (d, 1H), 7.82-7.72 (m, 3H), 7.41 (d, 2H), 5.08-4.98 (m, 1H), 3.98(dd, 1H), 3.84 (ddd, 1H), 3.75- 3.66 (m, 1H), 3.27-3.14 (m, 2H), 3.02(dd, 1H), 2.78-2.69 (m, 1H), 2.64-2.51 (m, 3H), 1.79-1.64 (m, 2H). m/z:407

Example 34 Diastereomeric Mixture of(2S)—N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamideand(2R)—N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide

i) tert-Butyl2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

rac-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (248 mg,1.01 mmol) and 4′-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile(Intermediate 1, 1200 mg, 0.81 mmol) were added to T3P (700 mg, 50%solution in DMF) in DMF (2 mL). TEA (640 μL, 4.54 mmol) was added andthe reaction stirred at rt for 18 h. After this time the reactionmixture was concentrated under reduced pressure. The resultant oil wasdissolved in EtOAc and washed successively with 2 M aqueous hydrochloricacid, saturated aqueous solution of sodium hydrogen carbonate and sodiumchloride solution. The organic extracts were dried (magnesium sulfate),filtered and concentrated under reduced pressure to afford the subtitledcompound as a yellow oil which was used without further purification inthe next step.

ii) Diastereomeric Mixture of(2S)—N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamideand(2R)—N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide

Prepared according to procedure in Method A step ii) using tert-butyl2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylateto afford the title compound as a white solid (150 mg, 50% over twosteps). The isolated compound was a mixture of two diastereomers, whichwere not separated. ¹H NMR (400 MHz, CDCl₃): δ 7.75-7.64 (m, 4H), 7.59(dd, 2H), 7.43 (dd, 2H), 7.30-7.22 (m, 1H), 5.25-5.11 (m, 1H), 4.12-4.06(m, 1H), 4.05-3.95 (m, 1H), 3.81-3.70 (m, 1H), 3.33 (ddd, 1H), 3.25-3.09(m, 2H), 3.08-3.00 (m, 1H), 2.98-2.81 (m, 2H), 1.92-1.75 (m, 2H) (oneexchangeable proton not observed).

LCMS (10 cm_ESCI_Formic_MeCN) t_(R) 2.58 (min) m/z 375 (MH⁺).

Example 35(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

i)tert-Butyl(2S)-2-({(2S)-1-amino-3-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]-1-oxopropan-2-yl}carbamoyl)-1,4-oxazepane-4-carboxylate

7-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinoxalin-2(1H)-one(Boronate ester 2, 100 mg, 0.37 mmol) and tert-butyl(2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate(Intermediate 4, 182 mg, 0.35 mmol) were dissolved in ACN (9 mL) andwater (0.4 mL). The reaction mixture was degassed under nitrogen for 30min before the addition of potassium carbonate (73 mg, 0.53 mmol) andPd(dppf)Cl₂.DCM (29 mg, 0.035 mmol). The reaction mixture was heated at80° C. for 1 h. After this time the reaction was concentrated underreduced pressure. Purified by silica gel column chromatography elutingwith 8% methanol in EtOAc to afford the subtitled compound as a brownoil (192 mg, 100%). Used without further purification in the next step.

ii) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

Burgess reagent (167 mg, 0.70 mmol) was added to a solution oftert-butyl(2S)-2-({(2S)-1-amino-3-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]-1-oxopropan-2-yl}carbamoyl)-1,4-oxazepane-4-carboxylate(192 mg, 0.35 mmol) in DCM (15 mL). The reaction mixture was stirred atrt for 24 h. After which time the reaction was transferred to aseparating funnel and washed with water. The organic extracts were dried(phase separator cartridge) and concentrated under reduced pressure. Theresultant solid was purified by silica gel column chromatography elutingwith 65% EtOAc in iso-hexane to afford a yellow oil. Trituration withdiethyl ether afforded the subtitled compound as an oil (101 mg, 54%).¹H NMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 7.95 (d, 1H), 7.67 (d, 2H),7.58 (dd, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 7.10-7.03 (m, 1H), 5.25-5.12(m, 1H), 4.23-4.10 (m, 3H), 3.77 (s, 3H), 3.54-3.49 (m, 3H), 3.28-3.19(m, 3H), 2.05-1.89 (m, 2H), 1.47 (s, 9H).

iii)(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate(101 mg, 0.19 mmol) was dissolved in formic acid (2 mL) and heated at50° C. for 10 min on a pre-heated stirrer hotplate. After this time thereaction was concentrated under reduced pressure, dissolved in DCM andwashed with saturated sodium hydrogen carbonate solution. The organicextract was run through a hydrophobic frit/phase separator andconcentrated under reduced pressure. The solid was purified by silicagel column chromatography eluting with 0-2% methanolic ammonia (7 N) inDCM to afford the title compound as a yellow solid (65 mg, 80%).

¹H NMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 7.95 (d, 1H), 7.65 (d, 2H),7.57 (dd, 1H), 7.47 (m, 3H), 7.21 (d, 1H), 5.22 (dt, 1H), 4.11 (dd, 1H),4.00 (dt, 1H), 3.75 (m, 5H), 3.32 (dd, 1H), 3.17 (m, 2H), 3.06 (dd, 1H),2.99-2.87 (m, 2H), 1.89-1.81 (m, 2H) (two exchangeable protons notobserved). LCMS (10 cm_ESCI_Formic_MeCN) t_(R) 2.38 (min) m/z 432 (WO.

Example 36(2S)-2-[(3S,4E)-6-(2,3-Dihydro-1H-indol-1-yl)-6-oxohex-4-en-3-yl]-1,4-oxazepane-2-carboxamidetrifluoroacetate

i) tert-Butyl(2S)-2-{[(3S,4E)-6-(2,3-dihydro-1H-indol-1-yl)-6-oxohex-4-en-3-yl]-carbamoyl}-1,4-oxazepane-4-carboxylate

HATU (2.33 g, 6.12 mmol) was added to(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid(Intermediate 3, 1.25 g, 5.10 mmol),[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-buten-1-yl]aminetrifluoroacetate (Intermediate 6 in WO2012109415, 1.76 g, 5.10 mmol) andDiPEA (4.45 ml, 25.5 mmol) in DCM (25 ml) at rt. The resulting mixturewas stirred at rt for 4 h. The reaction mixture was diluted with DCM(100 mL), and washed sequentially with 0.1 M aq. HCl (100 mL), saturatedaq. NaHCO₃ (100 mL), and saturated brine (100 mL). The organic layer wasdried over Na₂SO₄, filtered and evaporated to afford the sub-titledproduct (1.50 g, 64%). LC-MS m/z 358 (M-Boc+H⁺). A sample of the crudeproduct (190 mg, 0.42 mmol) was purified by preparative chiral-HPLC on aCHIRALPAK IC-3 column, eluting isocratically with 50% EtOH in hexane aseluent. Fractions containing the desired compound were evaporated todryness to afford the sub-titled product (180 mg, 95%) as a colourlessoil. LC-MS m/z 358 (M-Boc+H⁺).

TFA (2 mL, 26.0 mmol) was added to tert-butyl(2S)-2-{[(3S,4E)-6-(2,3-dihydro-1H-indol-1-yl)-6-oxohex-4-en-3-yl]carbamoyl}-1,4-oxazepane-4-carboxylate(180 mg, 0.39 mmol) in DCM (10 mL) at rt. The resulting solution wasstirred at rt for 4 h. The solvent was removed under reduced pressure.The crude product was purified by preparative Flash (C18 column), usingdecreasingly polar mixtures of water (containing 0.1% TFA) and MeCN aseluents. Fractions containing the desired compound were dried bylyophilization to afford the title product (100 mg, 54%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ 8.80-9.10 (m, 2H), 8.30 (d, 1H), 8.15 (d,1H), 7.10-7.30 (m, 2H), 6.95-7.10 (m, 1H), 6.70-6.85 (m, 1H), 6.45 (d,1H), 4.10-4.70 (m, 4H), 3.90-4.10 (m, 1H), 3.75-3.85 (m, 1H), 3.55-3.70(m, 1H), 3.05-3.40 (m, 5H), 1.90-2.10 (m, 2H), 1.50-1.75 (m, 2H), 0.85(t, 3H). LCMS m/z 358 (MH⁺).

Example 37(2S)-2-[(2E,4S)-1-(2,3-Dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]-1,4-oxazepane-2-carboxamidetrifluoroacetate

i) tert-Butyl(2S)-2-{[(2E,4S)-1-(2,3-dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]carbamoyl}-1,4-oxazepane-4-carboxylate

HATU (465 mg, 1.22 mmol) was added to(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid(Intermediate 3, 150 mg, 0.61 mmol),[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]aminetrifluoroacetate (Intermediate 13 in WO2012109415, 174 mg, 0.47 mmol)and DiPEA (0.427 mL, 2.45 mmol) in DMF (5.0 mL) at 0° C. The resultingsolution was stirred at rt for 2.5 h. The reaction mixture wasevaporated to dryness and redissolved in EtOAc (25 mL), and washedsequentially with saturated aq. NH₄Cl (4×20 mL), saturated brine (3×20mL), and water (3×20 mL). The organic layer was dried over Na₂SO₄,filtered and evaporated to afford crude sub-titled product (200 mg, 67%)as a yellow oil. LC-MS m/z 486 (MUFF). The crude product was usedwithout further purification in the next step.

TFA (0.635 mL, 8.24 mmol) was added to tert-butyl(2S)-2-{[(2E,4S)-1-(2,3-dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]carbamoyl}-1,4-oxazepane-4-carboxylate(200 mg, 0.41 mmol) in DCM (5.0 mL) at 0° C. The resulting solution wasstirred at rt for 2 h. The solvent was removed under reduced pressure.The crude product was purified by preparative HPLC (Waters XBridge PrepC18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), usingdecreasingly polar mixtures of water (containing 0.5% TFA) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title product (130 mg, 63%) as a yellow gum.

LC-MS m/z 386 (MH⁺). ¹H-NMR (300 MHz, CD₃OD): δ 8.15 (1H, d), 7.10-7.30(2H, m), 7.05 (1H, t), 6.75-6.90 (1H, m), 6.50 (1H, d), 4.60-4.80 (1H,m), 4.40-4.55 (1H, m), 4.10-4.30 (3H, m), 3.70-3.95 (2H, m), 3.15-3.50(5H, m), 2.05-2.25 (2H, m), 1.40-1.70 (3H, m), 0.95 (6H, t), 1.35 (1H,d) (two exchangeable protons not observed).

Pharmacological Activity Test A1: Fluorescence Assay for RecombinantHuman (RH) DPP1

The activity of DPP1 was determined by measuring the enzymatic releaseof aminomethyl coumarin (AMC) from the peptide substrate(H-Gly-Arg-AMC), which leads to an increase in fluorescence intensity atλex=350 nm and λem=450 nm. The assay was carried out in black 384 wellplates in a final volume of 50 μl at 22° C. The assay conditionscontained the following: 25 mM piperazine buffer pH 5.0; 50 mM NaCl, 5mM DTT; 0.01% (v/v) Triton X-100; 100 μM H-Gly-Arg-AMC and rhDPP1 (˜50pM). Potential inhibitors were made up in DMSO and then diluted in theassay to give a final concentration of not exceeding 1% (v/v) DMSO. A10-point half-log dilution series of the inhibitors (highestconcentration typically 10 μM) was tested and the pIC₅₀ determined usinga 4-parameter logistic equation in a non-linear curve fitting routine. Astandard DPP1 inhibitor,4-amino-N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide(WO2010/128324, Ex. 3) was used as a positive control in the assay.Routinely, inhibitors were pre-incubated with rhDPP1 for 30-60 min priorto the addition of the peptide substrate to start the reaction for afurther 60 min at 22° C. After that the plates were immediately read ina fluorescence plate reader using the above emission and excitationwavelengths [modified from Kam, C M, Gotz, M G, Koot, G, McGuire, M J,Thiele, D L, Hudig, D & Powers, J C (2004). Arch Biochem Biophys, 427,123-134 & McGuire, M J, Lipsky, P E & Thiele, D L (1992). Arch BiochemBiophys, 295, 280-288]. The results obtained are shown in Table 11 below(Examples 1-35).

Test A2: Fluorescence Assay for Recombinant Human (RH) DPP1

The activity of DPP1 was determined by measuring the enzymatic releaseof aminomethyl coumarin (AMC) from the peptide substrate(H-Gly-Arg-AMC), which leads to an increase in fluorescence intensity atλex=350 nm and λem=450 nm. The assay was carried out in black 384 wellplates in a final volume of 10 μl at rt. The assay conditions containedthe following: 25 mM piperazine buffer pH 5.0; 50 mM NaCl, 5 mM DTT;0.005 (v/v) Triton X-100; 50 μM H-Gly-Arg-AMC and 96.4 pM rhDPP1.Potential inhibitors were diluted in DMSO to generate 100× of the finalassay concentration. The compounds were tested at 10 concentrations withhalf-log dilution steps (highest concentration typically 1 μM) and witha final DMSO concentration of 1% (v/v). Routinely, inhibitors werepre-incubated with rhDPP1 for 30 min prior to the addition of thepeptide substrate to start the reaction for a further 30 min. Afterincubation the plates were read in a fluorescence plate reader using theabove emission and excitation wavelengths. The pIC₅₀ were determinedusing a 4-parameter logistic equation in a non-linear curve fittingroutine (Smartfit, Genedata Screener®). A standard DPP1 inhibitor,4-amino-N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide(WO2010/128324, Ex. 3) was used as a positive control and 1% (v/v) DMSOwas used as a negative control in the assay. [modified from Kam, C M,Gotz, M G, Koot, G, McGuire, M J, Thiele, D L, Hudig, D & Powers, J C(2004). Arch Biochem Biophys, 427, 123-134 & McGuire, M J, Lipsky, P E &Thiele, D L (1992). Arch Biochem Biophys, 295, 280-288]. The resultsobtained are shown in Table 11 below (Examples 36-37).

TABLE 11 Compound of Example DPP1 activity, pIC₅₀ 1 7.45 2 8.35 3 7.99 47.1 5 7.79 6 7.44 7 7.16 8 7.06 9 7.89 10 7.67 11 7.05 12 8.0 13 8.14 147.78 15 8.29 16 8.24 17 8.2 18 8.5 19 7.84 20 7.9 21 8.09 22 7.71 237.17 24 7.86 25 7.97 26 7.87 27 8.18 28 8.09 29 8.62 30 7.43 31 7.67 327.37 33 7.21 34 7.22 35 7.61 36 8.3 37 8.28

Aortic Binding

A number of compounds have been described in literature to be retainedselectively in the aorta in quantitative whole-body autoradiography(QWBA) studies, leading to concomitant ultra-structural changes whenexamined by electron microscopy (see e.g. muzolimine (Schmidt et al.1984, Biochem. Pharmacol., 33, 1915-1921)). Further, the α-amino amidenitrile4-amino-N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyrancarboxamide, disclosed as a DPP1 inhibitor (WO2010/128324, Ex. 3),showed a high level of aortic retention in rat QWBA studies. To assistthe design of DPP1 inhibitors with a decreased risk of binding toelastin rich tissues, such as the aorta, the in-vitro competitive aorticbinding assay disclosed below (Test B) was developed to facilitate theselection process. Reference compounds and selected compoundsrepresenting the present disclosure were tested in Test B and theresults obtained are shown in Table 12.

Test B: In-Vitro Competitive Aortic Tissue Binding Assay

Aortic homogenate was prepared from the thoracic aortae of Han Wistarrats. Freshly isolated to thoracic aortae were frozen, and later thawedand stripped of non-elastic material. Stripped aortae were then weighed,cut into small pieces and homogenised first with a rotor-statorhomogeniser; and then with a loose-fit, and then a tight-fit, Douncehomogeniser in Puck's saline (137 mM NaCl, 5.37 mM KCl, 4.17 mM NaHCO₃,and 5.55 mM D-glucose).

Homogenate concentration was adjusted to 30 mg/mL in Puck's saline, andaliquots were stored at −80° C. until use. Positive and negative controlcompounds and test compounds were made up to 100 mM in DMSO, and addedto 1 mL aliquots of aortic homogenate in Puck's saline for a finalconcentration of 100 μM. Homogenate samples were pre-incubated with testcompounds at 37° C., rotating, overnight.[¹⁴C]4-Amino-N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamidewas then added to all samples to a final concentration of 100 μM, andsamples were incubated at 37° C., rotating, for a further 2 h. Proteinwas precipitated from each sample by the addition of 10 mL acetone,pre-chilled to −20° C. Samples were left overnight at −20° C. to allowcomplete precipitation. Precipitate was pelleted by centrifugation at4,500×g at 4° C. for 20 min, an aliquot of supernatant was removed foranalysis, and the remainder of the supernatant discarded. Precipitatewas washed by resuspension in 10 mL 80% methanol in distilled water, andre-pelleted by centrifugation at 4,500×g at 4° C. for 20 min. Washingwas repeated for a total of 4 washes in 80% methanol, and 2 furtherwashes in 100% methanol, an aliquot of supernatant being removed foranalysis at each stage. After final wash, precipitate was air-dried, anddissolved overnight in 1 mL NCSII Tissue Solubiliser. 1 mL aliquots ofsupernatants were added to 5 mL Ultima Gold scintillation fluid (PerkinElmer, MA, U.S.A.), and 1 mL solubilised pellets were added to 5 mLHionic-Fluor scintillation fluid (Perkin Elmer, MA, U.S.A.).Radioactivity of samples was determined on a Beckman LS6500 multipurposescintillation counter (Beckman Coulter, IN, U.S.A.). On each occasion,4-amino-N-[(1S)cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamidewas run as a positive control, andN-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4-(methylsulfonyl)phenyl]acetamide(compound 1, WO2006/001751) and DMSO vehicle were run as negativecontrols. Duplicate samples were tested for each compound on eachexperimental occasion, and at least two experiments were run for eachtest compound. Mean radioactivity of the samples pre-incubated with DMSOvehicle control was taken to be 100% binding, and results for samplespre-incubated with other compounds were expressed as % difference fromvehicle control. 1-way ANOVA and Bonferroni's multiple comparison testswere performed to calculate significance of differences from vehiclecontrol.

The results obtained are shown in Table 12 below. The results arequantified into four different categories: strong binder, medium binder,binder and no binder.

TABLE 12 Aortic Tissue Compound Structure Binding WO2010/128324 (Ex. 3)

Strong binder (reference) WO2010/128324 (Example 17)

Strong binder WO2009/074829 (Example 96)

Medium binder WO2009/074829 (Example 24)

Binder Example 2

No binder Example 16

No binder

[¹⁴C]4-Amino-N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyrancarboxamide

i) 4-Bromobenzo-[¹⁴C]-nitrile

1-Bromo-4-iodobenzene (473 mg, 1.67 mmol) and copper(I)[¹⁴C]cyanide(1850 MBq, 77 mg, 0.84 mmol) were dissolved in 1-methylpyrrolidin-2-one(4 mL) and heated in the microwave for 3 h at 150° C. The reaction wasdiluted with EtOAc (150 ml) and washed with 2% aq ferric chloride (100ml), 2% w/v aq sodium thiosulphate (100 ml) and saturated brine (25mL×3). The organics were passed through a phase separator and thesolvent removed to afford the crude product. The crude material waspurified by silica gel column chromatography eluting with 2% EtOAc inisoheptane to afford the title compound as a white solid (442 MBq, 37mg, 24%).

ii) (S)-tert-Butyl4-(1-amino-3-(4′-[¹⁴C]-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate

(S)-tert-Butyl-4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate(243 mg, 0.47 mmol), Pd-118 (30.6 mg, 0.05 mmol) and potassium carbonate(195 mg, 1.41 mmol) were added to a flask under an atmosphere ofnitrogen. 4-Bromobenzo-[¹⁴C]-nitrile (973 MBq, 86 mg, 0.47 mmol) indegassed ACN (6 mL) was added to the reaction flask, followed by water(3 mL). The mixture was heated at 73° C. under nitrogen for 4 h andallowed to stand overnight at rt. The reaction was diluted with water(50 ml) and the product extracted into DCM (25 mL×4). The combinedorganics were washed with saturated brine (50 ml) and the organicportion passed through a phase separator containing magnesium sulphate.The organics were concentrated in vacuo to give a dark brown oil. Thecrude material was purified by silica gel column chromatography elutingwith 0-100% EtOAc in heptane to afford a gum which on trituration withether/heptane gave the title compound as an off-white solid (802 MBq,189 mg, 82%). m/z (ES+) 395 [M+2H-BOC]⁺

iii) (S)-tert-Butyl4-(1-cyano-2-(4′-[¹⁴C]-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate

(S)-tert-Butyl4-(1-amino-3-(4′-[¹⁴C]-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate(802 MBq, 189 mg, 0.38 mmol) was dissolved in DCM (4 mL) and stirredunder nitrogen at rt. Burgess reagent (137 mg, 0.57 mmol) was added andthe reaction was allowed to stir for 6.5 h. The crude mixture waspurified by silica gel column chromatography eluting with 25-100% EtOAcin heptane to give the title compound as a white solid (714 MBq, 164 mg,90%). ¹H NMR (500 MHz, DMSO-d₆): δ 1.38 (s, 9H), 1.55-1.77 (m, 2H),1.84-2.02 (m, 1H), 3.07-3.25 (m, 3H), 3.43-3.53 (m, 1H), 3.54-3.62 (m,1H), 5.04-5.13 (m, 1H), 7.04 (s, 1H), 7.43 (d, 2H), 7.71 (d, 2H), 7.87(d, 2H), 7.93 (d, 2H), 8.46 (s, 1H).

m/z (ES−) 475 [M−H]⁻

iv)(S)-4-Amino-N-(1-cyano-2-(4′-[¹⁴C]-cyanobiphenyl-4-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

(S)-tert-Butyl4-(1-cyano-2-(4′-[¹⁴C]-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate(133 MBq, 29 mg, 0.06 mmol) was added to a preheated solution of formicacid (500 μl, 13.04 mmol, 50° C.) and the reaction heated with stirringfor 15 min at 50° C. The reaction was rapidly cooled and added to acooled mixture of saturated sodium hydrogen carbonate (5 ml) and DCM (5ml). The aqueous portion was washed with two further aliquots of DCM (5ml) and the combined organics washed with water (10 ml) and dried oversodium sulphate. The organics were removed to give a colourless oil,which on trituration with ether gave a white solid. The crude mixturewas purified by silica gel column chromatography eluting with 0-2%methanol in DCM to give the title compound (93 MBq, 68%) which wasstored as an MeCN solution. ¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (d, 1H),1.20 (d, 1H), 1.73 (ddd, 1H), 1.89 (ddd, 1H), 3.18-3.25 (m, 2H), 3.45(dt, 1H), 3.53-3.66 (m, 3H), 5.02 (t, 1H), 7.43 (d, 2H), 7.71 (d, 2H),7.89 (dd, 4H).

m/z (ES+) 377 [M+H]⁺

1.-12. (canceled)
 13. An oral composition comprising a compound offormula (I),

and a disintegrant, wherein, R¹ is

R² is hydrogen, F, Cl, Br, OSO₂C₁₋₃ alkyl, or C₁₋₃ alkyl; R³ ishydrogen, F, Cl, Br, CN, CF₃, SO₂C₁₋₃alkyl, CONH₂ or SO₂NR⁴R⁵, whereinR⁴ and R⁵ together with the nitrogen atom to which they are attachedform a azetidine, pyrrolidine or piperidine ring; or R¹ is

X is O, S or CF₂; Y is O or S; Q is CH or N; R⁶ is C₁₋₃ alkyl, whereinsaid C₁₋₃ alkyl is optionally substituted by 1, 2 or 3 F and optionallyby one substituent selected from OH, OC₁₋₃ alkyl, N(C₁₋₃ alkyl)₂,cyclopropyl, or tetrapydropyran; R⁷ is hydrogen, F, Cl or CH₃; or apharmaceutically-acceptable salt thereof.
 14. The oral composition ofclaim 13, wherein R¹ is

X is selected from O, S or CF₂; Y is selected from O or S; Q is selectedfrom CH or N; R⁶ is C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F and optionally by one substituent selectedfrom OH, OC₁₋₃alkyl, N(C₁₋₃alkyl)₂, cyclopropyl, or tetrahydropyran; andR⁷ is selected from hydrogen, F, Cl or CH₃.
 15. The oral composition ofclaim 13, wherein, R¹ is

X is selected from O, S or CF₂; Y is selected from O or S; R⁶ isC₁₋₃alkyl, wherein said C₁₋₃alkyl is optionally substituted by 1, 2 or 3F and optionally by one substituent selected from OH, OC₁₋₃alkyl,N(C₁₋₃alkyl)₂, cyclopropyl, or tetrahydropyran; and R⁷ is selected fromhydrogen, F, Cl or CH₃.
 16. The oral composition of claim 13, wherein,R¹ is

or a pharmaceutically acceptable salt thereof.
 17. The oral compositionof claim 16, wherein, X is O; R⁶ is C₁₋₃ alkyl; and R⁷ is hydrogen; or apharmaceutically acceptable salt thereof.
 18. The oral composition ofclaim 13, wherein, R¹ is

X is O; R⁶ is C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted by 1, 2 or 3 F; and R⁷ is hydrogen.
 19. The oral compositionof claim 13, wherein, R¹ is

X is O; R⁶ is C₁₋₃alkyl; and R⁷ is hydrogen.
 20. The oral composition ofclaim 13, selected from the group consisting of:(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;4′-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-ylmethanesulfonate;(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4′-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazolyl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-(4-{3[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazolyl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indolyl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-2-(4′-Carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazolyl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazolyl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-1-Cyano-2-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-2-[4′-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;(2S)—N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide;(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;or(2S)—N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide;and pharmaceutically acceptable salts thereof.
 21. The oral compositionof claim 13 which is(2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide:

or a pharmaceutically acceptable salt thereof.
 22. The oral compositionof claim 13 which is(2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide:


23. A method for treating an obstructive disease of the airway,comprising orally administering to a patient in need thereof, the oralcomposition of claim
 13. 24. A method for treating an obstructivedisease of the airway, comprising orally administering to a patient inneed thereof, the oral composition of claim
 22. 25. The method of claim23, wherein the obstructive disease of the airway is bronchiectasis. 26.The method of claim 23, wherein the obstructive disease of the airway iscystic fibrosis.
 27. The method of claim 23, wherein the obstructivedisease of the airway is asthma.
 28. The method of claim 23, wherein theobstructive disease of the airway is chronic obstructive pulmonarydisease (COPD).
 29. The method of claim 24, wherein the obstructivedisease of the airway is bronchiectasis.
 30. The method of claim 24,wherein the obstructive disease of the airway is cystic fibrosis. 31.The method of claim 24, wherein the obstructive disease of the airway isasthma.
 32. The method of claim 24, wherein the obstructive disease ofthe airway is chronic obstructive pulmonary disease (COPD).
 33. The oralcomposition of claim 22, which is a tablet.
 34. The oral composition ofclaim 33, wherein the tablet is coated.